Pneumatic piston hydrostatic bioreactor for cartilage tissue engineering.

During exercise, mechanical loads from the body are transduced into interstitial fluid pressure changes which are sensed as dynamic hydrostatic forces by cells in cartilage. The effects of these loading forces in health and disease are of interest to biologists, but the availability of affordable equipment for in vitro experimentation is an obstacle to research progress. Here, we report the development of a cost-effective hydropneumatic bioreactor system for research in mechanobiology. The bioreactor was assembled from readily available components (a closed-loop stepped motor and pneumatic actuator) and a minimal number of easily-machined crankshaft parts, whilst the cell culture chambers were custom designed by the biologists using CAD and entirely 3 D printed in PLA. The bioreactor system was shown to be capable of providing cyclic pulsed pressure waves at a user-defined amplitude and frequency ranging from 0 to 400 kPa and up to 3.5 Hz, which are physiologically relevant for cartilage. Tissue engineered cartilage was created from primary human chondrocytes and cultured in the bioreactor for five days with three hours/day cyclic pressure (300 kPa at 1 Hz), simulating moderate physical exercise. Bioreactor-stimulated chondrocytes significantly increased their metabolic activity (by 21%) and glycosaminoglycan synthesis (by 24%), demonstrating effective cellular transduction of mechanosensing. Our Open Design approach focused on using 'off-the-shelf' pneumatic hardware and connectors, open source software and in-house 3 D printing of bespoke cell culture containers to resolve long-standing problems in the availability of affordable bioreactors for laboratory research.

Non-vitamin K antagonist oral anticoagulants, proton pump inhibitors and gastrointestinal bleeds.

OBJECTIVE: To evaluate if proton pump inhibitor (PPI) treatment reduces the risk of upper gastrointestinal bleeding (UGIB) in patients with atrial fibrillation (AF) treated with non-vitamin K antagonist oral anticoagulants (NOACs). DESIGN: We used a common protocol, common data model approach to conduct a cohort study including patients with AF initiated on a NOAC in Stockholm, Denmark and the Netherlands from April 2011 until July 2018. The outcome of interest was a UGIB diagnosed in a secondary care inpatient setting. We used an inverse probability weighted (IPW) Poisson regression to calculate incidence rate ratios (IRRs), contrasting PPI use to no PPI use periods. RESULTS: In 164 290 NOAC users with AF, providing 272 570 years of follow-up and 39 938 years of PPI exposure, 806 patients suffered a UGIB. After IPW, PPI use was associated with lower UGIB rates (IRR: 0.75; 95% CI: 0.59 to 0.95). On an absolute scale, the protective effect was modest, and was found to be largest in high-risk patients, classified as age 75-84 years (number needed to treat for 1 year (NNTY): 787), age ≥85 years (NNTY: 667), HAS-BLED score ≥3 (NNTY: 378) or on concomitant antiplatelet therapy (NNTY: 373). CONCLUSION: Concomitant treatment with a PPI in NOAC-treated patients with AF is associated with a reduced risk of severe UGIB. This indicates that PPI cotreatment can be considered, in particular among the elderly patients, patients with a HAS-BLED score ≥3, and/or in patients on concomitant antiplatelet therapy.

Use of antipsychotics in Denmark 1997-2018: a nation-wide drug utilisation study with focus on off-label use and associated diagnoses.

AIMS: Antipsychotics are primarily labelled for the treatment of severe mental illness and have documented clinical utility in certain neurological disorders or palliative care. However, off-label use of antipsychotics is common and increasing, and prior studies on antipsychotic utilisation have not specifically assessed users in neurology, palliative care or general practice. We aimed to explore diagnoses associated with antipsychotic use, treatment patterns and characteristics of users without diagnoses relevant to antipsychotic treatment. METHODS: Population-based study identifiying all users of antipsychotics in Denmark (pop 5.7 mio.) 1997-2018 in the Danish National Prescription Register (DNPR). Possible indications for antipsychotic therapy were evaluated using in- and outpatient contacts from the DNPR. Users were divided hierarchically into six groups: severe mental disorders (schizophrenia, bipolar-spectrum disorders), chronic mental disorders (dementias, mental retardation, autism), other mental disorders (depression-spectrum, anxiety and personality disorders, etc.), selected neurological diseases, cancer and antipsychotic users without any of these diagnoses. This last group was characterised regarding demographics, antipsychotic use, health care utilisation and likely antipsychotic treatment initiator in 2018. RESULTS: Altogether, 630 307 antipsychotic users were identified, of whom 127 649 had filled prescriptions during 2018. Users without diagnoses relevant to antipsychotic treatment comprised of the largest group (37%), followed by schizophrenia and bipolar-spectrum disorders (34%), other mental disorders (15%), dementia, autism and mental retardation (11%), cancer (2.2%) and neurological diagnoses (2.0%). Of 37 478 incident users in 2018, 39% had no diagnosis relevant to antipsychotic treatment, 7.9% had major depression, 7.7% neurotic/stress-related disorders and 7.5% dementia. Quetiapine was most commonly used, both overall (51%) and among users without diagnoses relevant to antipsychotic treatment (58%). Of 14 474 incident users in 2018 without diagnoses relevant to antipsychotic treatment, treatment was most likely initiated by a general practitioner (65%), with only 17% seeing a psychiatrist during the following year. As many as 18% of patients with adjustment disorders and 14% of those without relevant diagnoses for antipsychotic use, remained on antipsychotic treatment 5 years after their first prescription. CONCLUSIONS: Over one-third of antipsychotic users in Denmark did not have psychiatric, neurological or cancer diagnoses as possible indications for antipsychotic therapy. Many antipsychotics are initiated or prescribed in general practice, and a concerningly large subgroup without documented diagnoses relevant for antipsychotics continued to receive them. Rational prescribing, adequate side effect monitoring and further research into reasons for the observed antipsychotic use patterns and their risk-benefit ratio are needed.

Baseline findings of the population-based, randomized, multifaceted Danish cardiovascular screening trial (DANCAVAS) of men aged 65-74 years.

BACKGROUND: The challenge of managing age-related diseases is increasing; routine checks by the general practitioner do not reduce cardiovascular mortality. The aim here was to reduce cardiovascular mortality by advanced population-based cardiovascular screening. The present article reports the organization of the study, the acceptability of the screening offer, and the relevance of multifaceted screening for prevention and management of cardiovascular disease. METHODS: Danish men aged 65-74 years were invited randomly (1 : 2) to a cardiovascular screening examination using low-dose non-contrast CT, ankle and brachial BP measurements, and blood tests. RESULTS: In all, 16 768 of 47 322 men aged 65-74 years were invited and 10 471 attended (uptake 62·4 per cent). Of these, 3481 (33·2 per cent) had a coronary artery calcium score above 400 units. Thoracic aortic aneurysm was diagnosed in the ascending aorta (diameter 45 mm or greater) in 468 men (4·5 per cent), in the arch (at least 40 mm) in 48 (0·5 per cent) and in the descending aorta (35 mm or more) in 233 (2·2 per cent). Abdominal aortic aneurysm (at least 30 mm) and iliac aneurysm (20 mm or greater) were diagnosed in 533 (5·1 per cent) and 239 (2·3 per cent) men respectively. Peripheral artery disease was diagnosed in 1147 men (11·0 per cent), potentially uncontrolled hypertension (at least 160/100 mmHg) in 835 (8·0 per cent), previously unknown atrial fibrillation confirmed by ECG in 50 (0·5 per cent), previously unknown diabetes mellitus in 180 (1·7 per cent) and isolated severe hyperlipidaemia in 48 men (0·5 per cent). In all, 4387 men (41·9 per cent), excluding those with potentially uncontrolled hypertension, were referred for additional cardiovascular prevention. Of these, 3712 (35·5 per cent of all screened men, but 84·6 per cent of those referred) consented and were started on medication. CONCLUSION: Multifaceted cardiovascular screening is feasible and may optimize cardiovascular disease prevention in men aged 65-74 years. Uptake is lower than in aortic aneurysm screening.

The PARIS score can reliably predict 7-day all-cause mortality for both acute medical and surgical patients: an international validation study.

BACKGROUND: We believe errors in the risk assessment of acutely ill patients occur because only vital signs without concurrent functional capacity are considered. We, therefore, developed the PARIS risk score based on blood pressure, age, respiratory rate, loss of independence and oxygen saturation. AIM: Validation of the PARIS score in four independent cohorts from three countries. METHODS: Retrospective cohort study of acutely ill patients admitted to hospitals in Denmark, Ireland and Uganda. Vital signs and functional capacity (registered as ability to stand or walk or get into bed unaided) was recorded upon arrival. Patients were followed up for 7 days (Denmark and Ireland) or until discharge (Uganda) and mortality recorded. The discriminatory power (ability to identify patients at increased risk) was determined using area under the receiver operating characteristics curve (AUROC) and calibration (precision) using Hosmer-Lemeshow goodness of fit test. RESULTS: Out of 14 447 patients, 327 (2.3%) died within 7 days: median age was 59 (39-75) years and 7458 (51.8%) were female. Seven-day mortality increased from 0.3% with a score of 0-26.7% with a score of 5. The score's AUROC as 0.833 [95% confidence interval (95% CI) 0.811-0.856], 0.817 (95% CI 0.792-0.842) and 0.894 (95% CI 0.813-0.974) for all patients, medical patients and surgical patients, respectively. However, except for surgical patients, calibration of the score was poor. CONCLUSION: The PARIS score can identify both high and low risk acutely admitted medical and surgical patients, but calibration was poor for medical patients.

Association between use of phthalate-containing medication and semen quality among men in couples referred for assisted reproduction.

STUDY QUESTION: Does phthalate exposure from prescription drugs affect semen quality? SUMMARY ANSWER: Exposure to phthalate-containing drugs is associated with poor semen quality. WHAT IS KNOWN ALREADY: Phthalates and their metabolites have been shown to disrupt the hormone signalling in animal studies. One study has shown associations between medicinal phthalate exposure and poor semen quality, suggesting similar effects in humans. STUDY DESIGN, SIZE, DURATION: We included 18 515 males with poor semen quality (cases) and 31 063 males with normal semen quality (controls) registered in the Danish IVF Registry from 2006 to 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Exposure to phthalate-containing drugs was assessed from the Danish Register of Medicinal Product Statistics. Outcome measures were obtained at the first contact with the fertility clinic, and categorized according to the International Classification of Diseases (ICD-10). The association between current use of phthalate-containing medications <90 days prior to semen sampling and reduced semen quality was analysed using unconditional logistic regression, adjusting for potential confounders. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 57 cases and 72 controls redeemed at least one prescription for a drug containing ortho-phthalates in the 90 days before their first semen sample, yielding an adjusted odds ratio (OR) of 1.30 (95% CI: 0.91-1.85) for poor semen quality when compared to males exposed to phthalate-free generic drugs. Similarly, 81 cases and 78 controls exposed to a drug containing polymers had increased odds of poor semen quality (OR = 1.71, 95% CI: 1.24-2.35). Current exposure to polymer containing products from alimentary tract and metabolism drugs was associated with the highest OR of 2.80 (95% CI: 1.63-4.84). Comparing males exposed to drugs containing ortho-phthalates or polymers with males unexposed to prescription drugs, we found adjusted ORs of 1.32 (95% CI: 0.93-1.87) and 1.73 (95% CI: 1.26-2.36), respectively. We saw no clear relationship between degree of exposure and odds of poor semen quality. LIMITATIONS, REASONS FOR CAUTION: The reliance on ICD-10 based register data restricted our ability to relate phthalate exposure to detailed semen parameters. Furthermore, due to imperfections in the registry, we could only include the first semen sample and could not follow semen quality over time. WIDER IMPLICATIONS OF THE FINDINGS: Our results support the likely negative effect of phthalate exposure from medicinal drugs on semen quality. As exposures from medicinal products are readily avoidable, our findings may be of relevance to regulatory authorities. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by Odense University Hospital, Denmark (Grant number A1003). None of the authors declare conflict of interest.

The use of selective serotonin receptor inhibitors (SSRIs) is not associated with increased risk of endoscopy-refractory bleeding, rebleeding or mortality in peptic ulcer bleeding.

BACKGROUND: Observational studies have consistently shown an increased risk of upper gastrointestinal bleeding in users of selective serotonin receptor inhibitors (SSRIs), probably explained by their inhibition of platelet aggregation. Therefore, treatment with SSRIs is often temporarily withheld in patients with peptic ulcer bleeding. However, abrupt discontinuation of SSRIs is associated with development of withdrawal symptoms in one-third of patients. Further data are needed to clarify whether treatment with SSRIs is associated with poor outcomes, which would support temporary discontinuation of treatment. AIM: To identify if treatment with SSRIs is associated with increased risk of: (1) endoscopy-refractory bleeding, (2) rebleeding or (3) 30-day mortality due to peptic ulcer bleeding. METHODS: A nationwide cohort study. Analyses were performed on prospectively collected data on consecutive patients admitted to hospital with peptic ulcer bleeding in Denmark in the period 2006-2014. Logistic regression analyses were used to investigate the association between treatment with SSRIs and outcome following adjustment for pre-defined confounders. Sensitivity and subgroup analyses were performed to evaluate the validity of the findings. RESULTS: A total of 14 343 patients were included. Following adjustment, treatment with SSRIs was not associated with increased risk of endoscopy-refractory bleeding (odds ratio [OR] [95% Confidence Interval (CI)]: 1.03 [0.79-1.33]), rebleeding (OR [95% CI]: 0.96 [0.83-1.11]) or 30-day mortality (OR [95% CI]: 1.01 [0.85-1.19]. These findings were supported by sensitivity and subgroup analyses. CONCLUSIONS: According to our data, treatment with SSRIs does not influence the risk of endoscopy-refractory bleeding, rebleeding or 30-day mortality in peptic ulcer bleeding.

Hydrochlorothiazide use is strongly associated with risk of lip cancer.

BACKGROUND: The diuretic hydrochlorothiazide is amongst the most frequently prescribed drugs in the United States and Western Europe, but there is suggestive evidence that hydrochlorothiazide use increases the risk of lip cancer. OBJECTIVES: To study the association between use of hydrochlorothiazide and squamous cell carcinoma of the lip. METHODS: We conducted a case-control study using Danish nationwide registry data. From the Cancer Registry (2004-2012), we identified 633 case patients with squamous cell carcinoma (SCC) of the lip and matched them to 63 067 population controls using a risk-set sampling strategy. Hydrochlorothiazide use (1995-2012) was obtained from the Prescription Registry and defined according to cumulative use. Applying conditional logistic regression, we calculated odds ratios (ORs) for SCC lip cancer associated with hydrochlorothiazide use, adjusting for predefined potential confounders obtained from demographic, prescription and patient registries. RESULTS: Ever-use of hydrochlorothiazide was associated with an adjusted OR for SCC lip cancer of 2.1 (95% confidence interval (CI): 1.7-2.6), increasing to 3.9 (95%CI: 3.0-4.9) for high use (≥25 000 mg). There was a clear dose-response effect (P < 0.001), with the highest cumulative dose category of hydrochlorothiazide (≥100 000 mg) presenting an OR of 7.7 (95%CI: 5.7-10.5). No association with lip cancer was seen with use of other diuretics or nondiuretic antihypertensives. Assuming causality, we estimated that 11% of the SCC lip cancer cases could be attributed to hydrochlorothiazide use. CONCLUSIONS: Hydrochlorothiazide use is strongly associated with an increased risk of lip cancer.

Clopidogrel-Paclitaxel Drug-Drug Interaction: A Pharmacoepidemiologic Study.

Paclitaxel is mainly eliminated by CYP2C8 in the liver. CYP2C8 is strongly inhibited by the clopidogrel metabolite acyl-ß-D-glucuronide. To determine if this interaction has clinical relevance, we identified 48 patients treated with clopidogrel and paclitaxel using databases and a prescription register. Peripheral sensory neuropathy was retrospectively evaluated from medical charts and compared to that of 88 age- and sex-matched controls treated with paclitaxel and low-dose aspirin. By a cumulative dose of 1,500 mg paclitaxel, 35% of the patients had developed severe neuropathy. The overall hazard ratio between clopidogrel use and severe paclitaxel neuropathy was 1.7 (95% confidence interval, 0.9-3.0). Among those receiving a high-dose paclitaxel regimen, the hazard ratio was 2.3 (95% confidence interval, 1.1-4.5). Our study indicates that clopidogrel is associated with a clinically relevant increased risk of neuropathy in patients treated with high-dose paclitaxel.

The DanCavas Pilot Study of Multifaceted Screening for Subclinical Cardiovascular Disease in Men and Women Aged 65-74 Years.

OBJECTIVE/BACKGROUND: This pilot study of a large population based randomised screening trial investigated feasibility, acceptability, and relevance (prevalence of clinical and subclinical cardiovascular disease [CVD] and proportion receiving insufficient prevention) of a multifaceted screening for CVD. METHODS: In total, 2060 randomly selected Danish men and women aged 65-74 years were offered (i) low dose non-contrast computed tomography to detect coronary artery calcification (CAC) and aortic/iliac aneurysms; (ii) detection of atrial fibrillation (AF); (iii) brachial and ankle blood pressure measurements; and (iv) blood levels of cholesterol and hemoglobin A1c. Web based self booking and data management was used to reduce the administrative burden. RESULTS: Attendance rates were 64.9% (n = 678) and 63.0% (n = 640) for men and women, respectively. In total, 39.7% received a recommendation for medical preventive actions. Prevalence of aneurysms was 12.4% (95% confidence interval [CI] 9.9-14.9) in men and 1.1% (95% CI 0.3-1.9) in women, respectively (p < .001). A CAC score > 400 was found in 37.8% of men and 11.3% of women (p < .001), along with a significant increase in median CAC score with age (p = .03). Peripheral arterial disease was more prevalent in men (18.8%, 95% CI 15.8-21.8) than in women (11.2%, 95% CI 8.7-13.6). No significant differences between the sexes were found with regard to newly discovered AF (men 1.3%, women 0.5%), potential hypertension (men 9.7%, women 11.5%), hypercholesterolemia (men 0.9%, women 1.1%) or diabetes mellitus (men 2.1%, women 1.3%). CONCLUSION: Owing to the higher prevalence of severe conditions, such as aneurysms and CAC ≥ 400, screening for CVD seemed more prudent in men than women. The attendance rates were acceptable compared with other screening programs and the logistical structure of the screening program proved successful.

Use of antibiotics in childhood and risk of Type 1 diabetes: a population-based case-control study.

AIMS: To investigate whether the use of antibiotics from infancy to adolescence influences the risk of Type 1 diabetes. METHODS: We conducted a population-based case-control study, including all Type 1 diabetes cases in Denmark among children born between 1997 and 2012 (n = 1578). Odds ratios associating Type 1 diabetes with use of antibiotics were calculated using conditional logistic regression. RESULTS: Overall, we found no association between the use of antibiotics and risk of Type 1 diabetes. Furthermore, no associations were seen specifically for broad-spectrum, narrow-spectrum, bactericidal or bacteriostatic types of antibiotics or for the most frequently used individual classes of antibiotics. No differences were observed in subgroups defined by sex or by age at time of diagnosis. However, filling five or more antibiotic prescriptions in the first 2 years of life specifically was associated with a higher odds ratio of 1.35 (95% CI 1.10-1.64). This association appeared to be driven by exposure to broad-spectrum antibiotics within the second year of life. CONCLUSION: Antibiotic exposure in childhood is generally not associated with the risk of developing Type 1 diabetes. Future studies should investigate the effects of multiple exposures to broad-spectrum antibiotics during the second year of life.

Patterns of finasteride use in the male populations of four Nordic countries: A cross-national drug utilization study.

Objective Finasteride 5 mg is a drug used to treat prostate hyperplasia. Little is known about its pattern of usage. This cross-national analysis of individual-level data from Denmark, Finland, Norway and Sweden was undertaken to appraise its usage and describe cross-national differences. Materials and methods Individual-level data from nationwide prescription registers in Denmark (1995-2009), Finland (1997-2010), Norway (2004-2009) and Sweden (July 2005-2011) were used to examine cross-national finasteride utilization patterns in the adult male population (≥15 years). The study presents period prevalences, incidence rates, waiting time distributions and Lorenz curves. Results During the study period, 295,620 men had at least one prescription redemption of finasteride 5 mg, and there were approximately 3 million dispensing events of finasteride prescriptions in the four Nordic countries. Different patterns of finasteride use were observed among the four Nordic countries. The period prevalence was markedly higher in Finland and Sweden than in Denmark and Norway. In 2009, period prevalences were 18.2/1000 males in Finland and 12.0/1000 males in Sweden compared to 6.7/1000 males in Norway and 4.9/1000 males in Denmark. Incidence rates of finasteride use for Finland, Norway and Sweden were about three times that for Denmark in 2008-2009. Long-term use of finasteride was found in all four Nordic countries with a high ratio between prevalent and incident users. Conclusion Despite resemblances regarding political systems and healthcare services in the Nordic countries, differences in finasteride utilization were found across Denmark, Finland, Norway and Sweden.

Use of acid-suppressive therapy before anti-reflux surgery in 2922 patients: a nationwide register-based study in Denmark.

BACKGROUND: Guidelines recommend that patients with gastro-oesophageal reflux disease are adequately treated with acid-suppressive therapy before undergoing anti-reflux surgery. Little is known of the use of acid-suppressive drugs before anti-reflux surgery. AIM: To determine the use of proton pump inhibitors and H2 -receptor antagonists in the year before anti-reflux surgery. METHODS: A nationwide retrospective study of all patients aged ≥18 undergoing first-time anti-reflux surgery in Denmark during 2000-2012 using data from three different sources: the Danish National Register of Patients, the Danish National Prescription Register, and the Danish Person Register. RESULTS: The study population thus included 2922 patients (median age: 48 years, 55.7% male). The annual proportion of patients redeeming ≥180 DDD of acid-suppressive therapy increased from 17.0% 5 years before anti-reflux surgery to 64.9% 1 year before. The probability for inadequate dosing 1 year before surgery (<180 DDD) was significantly increased for younger patients, patients operated in the period 2000-2003, patients who had not undergone pre-surgical manometry, pH- or impedance monitoring, and patients who had not redeemed prescriptions on NSAID or anti-platelet drugs. CONCLUSION: Compliance with medical therapy should be evaluated thoroughly before planning anti-reflux surgery, as a high proportion of patients receive inadequate dosing of acid-suppressive therapy prior to the operation.

Statin use and risk of nonmelanoma skin cancer: a nationwide study in Denmark.

BACKGROUND: Evidence is conflicting regarding statin use and risk of basal cell (BCC) and squamous cell skin cancer (SCC). METHODS: Using Danish nationwide registries, we identified all patients with incident BCC/SCC during 2005-2009 and matched them to population controls. We computed odds ratios (ORs) for BCC and SCC associated with statin use. RESULTS: We identified 38,484 cases of BCC and 3724 cases of SCC. Statin ever use was associated with ORs of 1.09 (CI: 1.06-1.13) for BCC and 1.01 (CI: 0.91-1.11) for SCC. CONCLUSIONS: Statin use was not associated with risk of SCC. Residual confounding plausibly explains the marginally increased risk of BCC.

Dynamics of vitamin K antagonist and new oral anticoagulants use in atrial fibrillation: a Danish drug utilization study.

BACKGROUND: Detailed data on real-life utilization of vitamin K antagonists (VKAs) and new oral anticoagulants (NOACs) in atrial fibrillation are sparse. OBJECTIVES: To describe the dynamics of VKA and NOAC use: that is, (i) how patients moved in and out of, as well as between, use of VKAs and NOACs; (ii) how patients adhered to treatment; and (iii) which type of prescriber initiated, maintained, and changed treatment with VKAs and NOACs. METHODS: We conducted a drug utilization study in the region of southern Denmark (population 1.2 million) using prescription data. We included all subjects using VKAs or NOACs during the period of August 22, 2011, through June 30, 2013, restricted to subjects with a diagnosis of atrial fibrillation. RESULTS: We identified 20,911 subjects, of whom 20,769 and 1639 used VKAs and NOACs, respectively. The number of VKA users was stable at ~ 14,000 subjects during the study period, whereas the number of NOAC users increased to 903. The majority of NOAC users had previously used VKAs (n = 974), whereas 389 anticoagulant-naïve users initiated NOAC therapy. Among the latter, 51.2% had changed to VKAs within 6 months. 57.3% of VKA users were initiated by a hospital physician, whereas maintenance treatment was predominantly handled by the patient's general practitioner (97.6%). Switches from NOAC to VKA were initiated by a general practitioner in 69.2% of the cases. For users of NOACs, these numbers were 73.5%, 94.0%, and 63.3%. CONCLUSIONS: A large proportion of NOAC users switch to a VKA within a short time frame. The reasons for this are not clear.

Use of self-controlled designs in pharmacoepidemiology.

Self-controlled observational study designs, such as the case-crossover design and the self-controlled case series, are reviewed, and their respective rationale, strengths and limitations are compared. Although no single design is generally superior to the others, they share the trait of being robust towards confounders that are stable over time. The self-controlled designs can be particularly useful when using secondary healthcare data for pharmacoepidemiological research and might be useful in screening for adverse drug effects. The main limitations of self-controlled designs are that they are amenable only to transient effects; some may be inefficient with long-term exposure; and they may be sensitive towards trends in exposure.

Myasthenia and risk of cancer: a population-based case-control study.

BACKGROUND AND PURPOSE: To evaluate the association between having non-thymoma myasthenia and the risk of extra-thymic cancer in a population-based setting. METHODS: A nationwide case-control study was conducted in Denmark based on medical registries. The study included all cases with a first time diagnosis of cancer during 2000-2009. Each case was matched by birth year and gender with eight population controls using risk set sampling. Subjects with myasthenia were identified through a validated register-based algorithm. Conditional logistic regression was used to compute crude and adjusted odds ratios (ORs), with 95% confidence intervals (CIs), for cancer associated with a prior diagnosis of myasthenia. RESULTS: In all, 233 437 cases and 1 867 009 controls were identified. A total of 80 cases and 518 controls had a prior diagnosis of myasthenia. Myasthenia was not associated with an increased risk of overall cancer (OR 1.1; 95% CI 0.9-1.4). Adjusted ORs for major cancer sites were also close to unity, whereas an elevated risk of lymphomas was observed (OR 2.0; 95% CI 0.8-5.5). Early-onset myasthenia was associated with a slightly increased OR for overall cancer (1.5; 95% CI 1.0-2.3); however, this estimate was based on small numbers. CONCLUSIONS: Non-thymoma myasthenia was not associated with an increased risk of overall cancer. Larger studies are necessary to evaluate the association between myasthenia and risk of lymphoma and the potential effect modification by age of myasthenia onset in relation to cancer risk.

Risk of non-melanoma skin cancer in myasthenia patients treated with azathioprine.

BACKGROUND AND PURPOSE: The association between use of azathioprine and risk of non-melanoma skin cancer (NMSC) in patients with myasthenia was evaluated in a nationwide setting. Treatment of autoimmune myasthenia frequently involves long-term exposure to immunosuppressants, including azathioprine. Use of azathioprine increases the risk of NMSC in organ recipients and probably also in patients with other autoimmune disorders. No previous study has specifically investigated the risk of NMSC in myasthenia patients treated with azathioprine. METHODS: This is a case-control study based on Danish population-based registries. Cases were myasthenia patients with a first time diagnosis of NMSC during 2004-2009. Age- and sex-matched controls were selected amongst myasthenia patients with no history of cancer using incidence density sampling. Prior use of azathioprine in cases and controls was assessed through prescription records (1995-2009). Conditional logistic regression was used to calculate odds ratios (OR) with 95% confidence intervals (CI) for skin cancer associated with a high cumulative dose (≥150 g) or long-term use (≥5 years) of azathioprine, adjusted for confounders. RESULTS: Thirty NMSC cases and 360 matched controls were identified. Ever use of azathioprine was associated with a considerably increased risk of NMSC (OR 3.3, 95% CI 1.5-7.3) that was even more apparent in patients with high cumulative dose (OR 4.6, 95% CI 1.7-12.5) or long-term (OR 4.8; 95% CI 1.7-13.6) use of azathioprine. CONCLUSION: Azathioprine use in patients with myasthenia is associated with an increased risk of NMSC.

Prescription of antidepressants is increased in Danish patients with polycystic ovary syndrome and is associated with hyperandrogenism. A population-based cohort study.

OBJECTIVE: Quality of life is impaired in polycystic ovary syndrome (PCOS). In this study, we compared the time to first prescription of antidepressants (ADM) in PCOS vs two control groups. DESIGN: Register-based cohort study. PATIENTS: One thousand and one hundred and twenty-four premenopausal women with hirsutism and/or PCOS, premenopausal women with hypertension (HT, n = 301), and age- and sex-matched population controls (controls, n = 4110). MEASUREMENTS: Prescriptions for ADM on secondary care contacts from regional registers. RESULTS: The median age at cohort entry in PCOS, HT and controls was 29, 34 and 29 years, respectively. Among PCOS, HT and controls, 227 (20%), 74 (25%) and 633 (15%), respectively, had prescriptions of ADM. The median time to first prescription of ADM in the PCOS, HT and control cohorts was 6·8, 6·6 and 7·2 years, respectively. The adjusted hazard ratio for time to prescription of ADM for HT vs PCOS was 1·36 [95% CI (1·02-1·82)], P = 0·039, and for controls vs PCOS, it was 0·75 [95% CI (0·64-0·88)], P < 0·001. Within patients with PCOS, hyperandrogenism contributed significantly to the model, likelihood ratio test P = 0·009. The adjusted hazard ratio for hyperandrogenism vs no hyperandrogenism was 1·97 (1·12-3·45), P = 0·018. CONCLUSION: Patients with PCOS had moderately but significantly decreased time to first prescription of ADM compared with age-matched healthy women, whereas patients with HT had the shortest time to prescription. In PCOS, prescription of ADM was associated with the presence of hyperandrogenism.