Danish Case-control Study Research Articles

82-OR: Association of Diabetic Complications and Various Comorbidities with Major Adverse Cardiovascular Events in Type 2 Diabetes and Their Development over Time—A Danish Registry-Based Case-Control Study

82-OR: Association of Diabetic Complications and Various Comorbidities with Major Adverse Cardiovascular Events in Type 2 Diabetes and Their Development over Time—A Danish Registry-Based Case-Control Study

Preadmission morbidity and healthcare utilization among older adults with potentially avoidable hospitalizations: a Danish case–control study

Key summary pointsAimExamine preadmission diagnoses, medication use, and preadmission healthcare utilization among older adults prior to a first potentially avoidable hospitalization.FindingsOur analysis revealed that preadmission morbidity, medication use, and a high and accelerating number of healthcare contacts are associated with potentially avoidable hospitalizations.MessagePreadmission morbidity and a high number of contacts with general practitioners are associated with potentially avoidable hospitalizations, which highlights the need for tailored clinical initiatives for older adults.

Discovery of potential plasma protein biomarkers for ventricular fibrillation due to first ST-elevation myocardial infarction via proteomics

Abstract Background Although most sudden cardiac deaths are a consequence of ventricular fibrillation (VF) subsequent to myocardial infarction, the underlying biological mechanisms of VF in the setting of ischemia are largely unknown. We used an unbiased mass-spectrometry (MS)-based proteomic approach to improve our understanding of the molecular VF mechanisms. Purpose We aimed to identify and characterize proteins that are associated with VF during first ST-elevation myocardial infarction (STEMI). Methods We included 230 participants from a Danish ongoing case-control study on patients with first STEMI with VF (case, n=110) and without VF (control, n=120) before guided catheter insertion for primary percutaneous coronary intervention. Using MS-based proteomics on plasma samples collected within 24h of symptom onset, we investigated the plasma proteome. After quality control, one patient was excluded and the difference in the quantitative proteome composition between cases and controls were analysed using t-tests, and further corrected for multiple comparison using the Benjamini-Hochberg procedure (q-value). Cardiac enzymes and anterior infarct location were used in a subset as a proxy for large myocardial damage. Results In 229 STEMI patients (72% men, median age 62 years (interquartile range (IQR): 54-70)), a total of 401 unique proteins were identified with a median of 257 proteins (IQR: 244-281) quantified per patient. A total of 26 proteins were associated with VF, these proteins were involved in several biological processes. The most frequent processes were blood coagulation, hemostasis and immunity. After correcting for multiple testing, two up-regulated proteins remained significantly associated with VF, actin beta-like 2 (ACTBL2, FC 2.25, p<0.001, q=0.023) and coagulation factor XIII-A (F13A1, FC 1.48, p<0.001, q=0.023). The most up-regulated protein was ACTBL2, and the second most up-regulated protein was actin alpha 2 (ACTA2, FC 1.72, p=0.001, q=0.073). None of the three proteins were correlated with cardiac enzymes or anterior infarct location. Conclusion VF due to first STEMI was significantly associated with two up-regulated proteins (ACTBL2 and F13A1). None of these proteins were correlated with infarct size which could reflect novel underlying molecular VF mechanisms.

Discovery of plasma proteins associated with ventricular fibrillation during first ST-elevation myocardial infarction via proteomics.

The underlying biological mechanisms of ventricular fibrillation (VF) during acute myocardial infarction are largely unknown. To our knowledge, this is the first proteomic study for this trait, with the aim to identify and characterize proteins that are associated with VF during first ST-elevation myocardial infarction (STEMI). We included 230 participants from a Danish ongoing case-control study on patients with first STEMI with VF (case, n = 110) and without VF (control, n = 120) before guided catheter insertion for primary percutaneous coronary intervention. The plasma proteome was investigated using mass spectrometry-based proteomics on plasma samples collected within 24 h of symptom onset, and one patient was excluded in quality control. In 229 STEMI patients {72% men, median age 62 years [interquartile range (IQR): 54-70]}, a median of 257 proteins (IQR: 244-281) were quantified per patient. A total of 26 proteins were associated with VF; these proteins were involved in several biological processes including blood coagulation, haemostasis, and immunity. After correcting for multiple testing, two up-regulated proteins remained significantly associated with VF, actin beta-like 2 [ACTBL2, fold change (FC) 2.25, P < 0.001, q = 0.023], and coagulation factor XIII-A (F13A1, FC 1.48, P < 0.001, q = 0.023). None of the proteins were correlated with anterior infarct location. Ventricular fibrillation due to first STEMI was significantly associated with two up-regulated proteins (ACTBL2 and F13A1), suggesting that they may represent novel underlying molecular VF mechanisms. Further research is needed to determine whether these proteins are predictive biomarkers or acute phase response proteins to VF during acute ischaemia.

Utilization of healthcare prior to endometriosis diagnosis: a Danish case-control study.

Do women with endometriosis have higher utilization of primary and secondary healthcare prior to diagnosis compared to women without endometriosis? Women with a hospital-based diagnosis of endometriosis had an overall higher utilization of both primary and secondary healthcare in all 10 years prior to diagnosis. Endometriosis is associated with a diagnostic delay, but only a few studies have investigated the potential consequences of this delay with regard to the utilization of healthcare. To the best of our knowledge, no study has investigated it in a period corresponding to the estimated diagnostic delay. This national Danish registry-based case-control study included 129 696 women. Cases were women with a first-time hospital-based diagnosis of endometriosis between 1 January 2000 and 31 December 2017. We identified 21 616 cases using density sampling. Each case was matched on age at the date of diagnosis (index date) to five women without diagnosed endometriosis (n = 108 080). The utilization of healthcare was assessed for the 10 years before the index. Cases had significantly higher use of healthcare in all 10 years preceding the index. The mean number of yearly contacts with the GP was 9.99 for cases and 7.85 for controls, with an adjusted incidence rate ratio of 1.28 (1.27; 1.29). For hospital contacts, the association increased slightly in the first 9 years and was most profound in the last year preceding index when the adjusted incidence rate ratio was 2.26 (95% CI 2.28; 2.31). We were not able to include women with an endometriosis diagnosis from the general practitioner or private gynaecologist. Therefore, our results are only applicable to hospital-based diagnoses of endometriosis. We do not have information on the specific reasons for contacting the healthcare providers and we can therefore only speculate that the higher utilization of healthcare among cases was related to endometriosis. This study is in agreement with the other known studies on the subject. Future studies should include specific reasons for contacting the healthcare system and thereby identify any specific contact patterns for women with endometriosis. With this knowledge, healthcare professionals could be better at relating certain healthcare seeking behaviour to endometriosis earlier and thereby reduce the time from onset of symptoms to diagnosis. This study is supported by grants from the project 'Finding Endometriosis using Machine Learning' (FEMaLe/101017562), which has received funding from The European Union's Horizon 2020 research and innovation program and Helsefonden (21-B-0141). K.Z. report grants from Bayer AG, Roche Inc. and Volition, royalties from Oxford-Bayer scientific collaboration in gynaecological therapies, non-financial collaboration with the World Endometriosis Society and World Endometriosis Research Foundation and is a Wellbeing of Women research advisory committee member. All this is outside the submitted work. The other authors have no conflict of interest to declare. N/A.

Use of statins and risk of myeloproliferative neoplasms: a Danish nationwide case-control study.

Previous studies have indicated a possible cancer-protective effect of statins in solid cancers; however, this has never been investigated in myeloproliferative neoplasms (MPNs). We aimed to investigate the association between statin use and the risk of MPNs in a nested nationwide case-control study, using Danish national population registries. Information on statin use was obtained from the Danish National Prescription Registry, and patients diagnosed with MPNs between 2010 and 2018 were identified from the Danish National Chronic Myeloid Neoplasia Registry. The association between statin use and MPNs was estimated using age- and sex-adjusted odds ratios (ORs) and fully adjusted ORs (aORs), adjusting for prespecified confounders. The study population included 3816 cases with MPNs and 19 080 population controls (5:1) matched for age and sex using incidence density sampling. Overall, 34.9% of the cases and 33.5% of the controls ever used statins, resulting in an OR for MPN of 1.07 (95% confidence interval [CI], 0.99-1.16) and an aOR of 0.87 (95%CI, 0.80-0.96), respectively. 17.2% were categorized as long-term users (≥5 years) among the cases compared with 19.0% among controls, yielding an OR for MPN of 0.90 (95%CI, 0.81-1.00) and an aOR of 0.72 (95%CI, 0.64-0.81). Analysis of the effect of the cumulative duration of statin use revealed a dose-dependent response, and the association was consistent for sex, age, and MPN subgroups and across different statin types. Statin users were associated with significantly lower odds of being diagnosed with an MPN, indicating a possible cancer-preventive effect of statins. The retrospective of this study precludes causal inferences.

Upper-Extremity Impairments in Type 1 Diabetes: Results From a Controlled Nationwide Study.

This study aimed to identify current and lifetime prevalence of upper-extremity impairments (UEIs) among individuals with type 1 diabetes and explore factors associated with UEIs. In a Danish cross-sectional nationwide case-control study, data on UEIs and health behavior were paired with data on sociodemographics and clinical factors from national registers. Participants included individuals with type 1 diabetes (n = 2,245) and a control group (n = 841). Differences between groups were assessed using binomial proportions and multivariable logistic regression. Compared with controls, individuals with type 1 diabetes were significantly (P < 0.05) more likely to experience frozen shoulder (odds ratio [OR] 3.5), carpal tunnel syndrome (OR 3.5), trigger finger (OR 5.0), and Dupuytren contracture (OR 4.3). They were also more likely to have several coexisting impairments than the control group (P < 0.01). Diabetes duration was associated with all four impairments. UEIs are common, particularly among individuals with type 1 diabetes.

Use of methotrexate and risk of skin cancer: a nationwide case–control study

BackgroundMethotrexate (MTX) use has been suspected of increasing the risk of skin cancer. The aim of this investigation was to examine the association between the use of MTX and the risk of basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC) and cutaneous malignant melanoma (CMM).MethodsIn a nationwide Danish case–control study, we identified incident, histologically verified cases of BCC (n = 131,447), cSCC (n = 18,661) or CMM (26,068) from 2004 to 2018. We matched 10 controls to each case on sex and birth year using risk-set sampling and computed crude and adjusted odds ratios (ORs) using conditional logistic regression for the use of MTX (≥2.5 g) compared with never-use.ResultsUse of MTX was associated with increased risk of BCC, cSCC and CMM with adjusted ORs of (95% confidence interval) 1.29 (1.20–1.38), 1.61 (1.37–1.89) and 1.35 (1.13–1.61), respectively. For BCC and cSCC, ORs increased with higher cumulative doses. When restricting the study population to patients with psoriasis, the ORs were 1.43 (1.23–1.67), 1.18 (0.80–1.74) and 1.15 (0.77–1.72), respectively.ConclusionsWe observed an increased risk of BCC and cSCC associated with the use of MTX with evidence of a dose–response pattern; however, the association was not consistent when restricting the study population to patients with psoriasis.

Depression related to hormonal contraceptive use as an early indicator of postpartum depression susceptibility: a danish nationwide case-control study

Depression related to hormonal contraceptive use as an early indicator of postpartum depression susceptibility: a danish nationwide case-control study

The risk of childhood brain tumors associated with delivery interventions: A Danish matched case-control study

BackgroundHead trauma has been associated with increased brain tumor risk in adults. Instrument assisted delivery can be a cause of head trauma in newborns. The goal of this study was to determine if instrument-assisted deliveries influenced the odds of childhood brain tumors in Denmark. MethodsWe conducted a matched case-control study of childhood (<20 years) brain tumors in Denmark born between 1978 and 2013 and diagnosed 1978–2016. A total of 1678 brain tumor cases were identified and 25 controls were matched to each case based on the child’s sex and birth date (N = 40,934). Conditional logistic regression was used to estimate effects (odds ratios (OR) and 95% confidence intervals (95%CI)) for variables of interest. ResultsCompared to children birthed by spontaneous vaginal delivery, children who later developed ependymomas (N = 118) had a greater likelihood of having experienced vacuum assisted deliveries (OR=1.74, 95% CI 1.02–2.96). Forceps use was low, and declined across the study period. We did not observe an overall increase in all CNS tumors (combined) with either vacuum delivery (OR=0.99, 95% CI 0.84–1.18) or forceps delivery (OR=1.26, 95% CI 0.78–2.03). ConclusionOur findings suggest an association between vacuum assisted deliveries and ependymomas.

Hypoxia-inducible factor-1\u03b1 expression and breast cancer recurrence in a Danish population-based case control study

BackgroundHypoxia-inducible factor-1α (HIF-1α) is a transcription factor that facilitates the adaptation of cancer cells to hypoxic conditions and may be prognostic of breast cancer recurrence. We evaluated the association of HIF-1α expression with breast cancer recurrence, and its association with timing of breast cancer recurrence.MethodsIn this population-based case-control study, we included women diagnosed with stage I–III breast cancer between 1985 and 2001, aged 35–69 years, registered in the Danish Breast Cancer Group. We identified 541 cases of breast cancer recurrence among women with estrogen receptor (ER)-positive disease who were treated with tamoxifen for at least 1 year (ER+ TAM+). We also enrolled 300 breast cancer recurrence cases among women with ER-negative disease, not treated with tamoxifen, who survived at least 1 year (ER−/TAM−). Controls were recurrence-free breast cancer patients at the time of case diagnosis, matched to recurrence cases on ER/TAM status, date of surgery, menopausal status, cancer stage, and county of residence. Expression of HIF-1α was measured by immunohistochemistry on tissue microarrays. We fitted logistic regression models to compute odds ratios (ORs) and 95% confidence intervals (CIs) associating HIF-1α expression with recurrence, and with timing of recurrence.ResultsHIF-1α expression was observed in 23% of cases and 20% of controls in the ER+/TAM+ stratum, and in 47% of cases and 48% of controls in the ER−/TAM− stratum. We observed a near-null association between HIF-1α expression in both ER/TAM groups (ER+/TAM+ OR = 1.21, 95%CI 0.88, 1.67 and ER−/TAM− OR = 0.97, 95%CI 0.68, 1.39). HIF-1α expression was not associated with time to recurrence among women in the ER+/TAM+ stratum, but was associated with early recurrence among women in the ER−/TAM− stratum.ConclusionIn this study, HIF-1α expression was not associated with breast cancer recurrence overall but may be associated with early recurrence among women diagnosed with ER− breast cancer.

Autoimmune diseases in microscopic colitis: A Danish nationwide case-control study.

The association between autoimmune diseases and microscopic colitis remains uncertain. To describe the association between autoimmune diseases and microscopic colitis by using a matched case-control design based on nationwide registry data. All adult Danish patients with a diagnosis of microscopic colitis from 2001 to 2018 were identified from nationwide registries. Odds of autoimmune diseases were compared between cases with microscopic colitis and sex- and age-matched controls from the background population in a 1:10 ratio and evaluated by logistic regression calculating odds ratios (OR) with 95% confidence intervals (CI) adjusted for comorbidity. Analyses were stratified according to sex, age and the subtypes of lymphocytic and collagenous colitis. We identified 15597 cases with microscopic colitis and matched to 155910 controls. In total, 3491 (22%) of patients with microscopic colitis had concomitant autoimmune disease compared to 16521 (11%) of controls (OR, 2.46; 95% CI, 2.36-2.56). Adjusting for comorbidities reduced the OR to 2.09 (95% CI, 2.01-2.19). Analyses showed increased ORs with 16 different autoimmune diseases, particularly of gastrointestinal and endocrine origin, and connective tissue disorders. The highest ORs were for coeliac disease (OR=10.15; 95% CI, 8.20-12.6), Crohn's disease (OR=2.47; 95% CI, 2.10-2.91) and ulcerative colitis (OR=6.73; 95% CI, 6.20-7.30). In stratified analyses younger age at diagnosis and collagenous colitis were associated with higher odds. Using nationwide registry data, microscopic colitis was associated with a wide range of autoimmune diseases, especially of gastrointestinal origin. The results suggest an autoimmune predisposition to microscopic colitis.

Spatial and temporal patterns of Lyme Neuroborreliosis on Funen, Denmark from 1995\u20132014

In Europe, Lyme neuroborreliosis (LNB) is the most severe manifestation of Lyme borreliosis and has recently been added to the communicable disease surveillance list for EU/EEA by the European Commission. In Northern Europe, LNB is primarily caused by the spirochete Borrelia garinii and transmitted by the tick Ixodes ricinus. This Danish observational epidemiologic case-control study includes every identified LNB patient (n = 401) on Funen, Denmark, from 1995-2014. We display spatial and temporal LNB incidence variation, seasonal distribution of cases and local spatial case clustering. Seasonal patterns show LNB symptom-onset peaking in July and a significant seasonal difference in number of cases (p < 0.01). We found no significant change in seasonality patterns over time when dividing the study period into 5-year intervals. We identified a significant local geographical hot-spot of cases with a relative risk of 2.44 (p = 0.013). Analysis revealed a significantly shorter distance to nearest forest for cases compared with controls (p < 0.001). We present a novel map of the focal geographical distribution of LNB cases in a high endemic borreliosis area. Continued studies of case clustering in the epidemiology of LNB are of key importance in guiding intervention strategies.

Association of insulin regimens with severe hypoglycaemia in patients with type 1 diabetes: A Danish case-control study.

To evaluate the risk of severe hypoglycaemia for patients with Type 1 diabetes (T1D) when exposed to insulin regimens including human insulin only or insulin analogues. A total of 19 896 patients with T1D were extracted from the Danish National Patient Register. Of these, 6379 T1D patients experiencing 1 of more severe hypoglycaemic episodes (total of 17 242 episodes) were matched 1:1 with T1D patients without severe hypoglycaemia. A logistic regression model with last insulin regimen used as exposure was constructed to analyse the effect on severe hypoglycaemia. People on a basal-bolus regimen with insulin analogues had a reduced risk of severe hypoglycaemia of 39% (odds ratio: 0.61, 95% confidence interval: 0.54-0.68) compared to patients on a basal-bolus human insulin only regimen. Furthermore, patients on a premixed regimen containing an insulin analogue had a 58% (odds ratio: 0.42, 95% confidence interval: 0.36-0.49) reduced risk of severe hypoglycaemia compared to patients on premixed human insulin only. This study indicates that use of a basal-bolus insulin regimen with an insulin analogue is safer with respect to severe hypoglycaemia in patients with T1D than the use of a basal-bolus human insulin only regimen.

No decrease in fracture risk despite 15 years of treatment evolution for multiple myeloma patients: A Danish nationwide case-control study.

While treatment strategies for multiple myeloma have evolved radically over the last decades, little is known about the risk of fractures for symptomatic multiple myeloma patients over time. To determine the effect of different treatment periods (1996-2000, 2001-2006 and 2007-2011) on the risk of fractures in patients with multiple myeloma. This retrospective case-control study included patients with multiple myeloma in Denmark, using the Danish National Health Service. Cases were defined as patients who had sustained a fracture between 1996 and 2011, and controls were those without a fracture. Exposure was defined as an ICD code for multiple myeloma. Vertebral fractures, gender, and age were considered in secondary analyses. Conditional logistic regression was used to estimate odd ratios (ORs) of fracture risk, and the analyses were adjusted for comorbidities and recent drug use. The study population consisted of 925,341 cases, and the same number of matched controls, of whom 1334 patients with multiple myeloma. Among cases, the risk of any fracture was higher in multiple myeloma patients compared to patients without multiple myeloma (any fracture: ORadj[95% CI] 1996-2000: 1.7[1.3-2.3]; 2001-2006: 1.3[1.1-1.6]; 2007-2011: 1.7[1.4-2.2]). Although fractures were mainly non-vertebral, the risk of vertebral fractures in particular was higher in multiple myeloma patients (vertebral fracture: ORadj[95% CI] 1996-2000: 3.5[1.4-8.6]; 2001-2006: 4.0[1.9-8.2]; 2007-2011: 3.0[1.6-5.7]). Despite new treatment strategies and improved supportive care, this study showed no decreased fracture risk for multiple myeloma patients over time. New treatment strategies, even if they have a positive impact on overall survival, offer no guarantee for a corresponding reduction in bone lesions.

Urinary tract infections and risk of squamous cell carcinoma bladder cancer: A Danish nationwide case-control study.

Schistosoma haematobium infection can lead to squamous cell carcinomas (SCC) of the bladder. Whether this also applies to more common urinary tract infections (UTIs) is unclear. We therefore aimed to investigate the association between UTIs, reflected by the use of specific antibiotics and risk of SCC of the bladder. We conducted a Danish nationwide case-control study and identified histologically verified bladder cancer cases (2000-2015; n = 12,271) and age- and sex-matched cancer-free controls. We computed odds ratios (ORs) with 95% confidence intervals (CI) associating the use of UTI-specific antibiotics with SCC bladder cancer, using conditional logistic regression. We applied a 2-year lag-time to minimize reverse causation. To aid interpretation, similar analyses were performed for other bladder cancer types and other antibiotics. We identified 333 SCC cases (2.7% of all bladder cancers). Compared to no use (0-1 prescription), high-use (≥10 prescriptions) of UTI-specific antibiotics was associated with SCC with an OR of 11.4 (CI 7.6-17.2) and a clear dose-response pattern (ptrend < 0.001). Use of phenoxymethylpenicillin, an antibiotic not used against UTIs, was not associated with SCC after adjustment for use of UTI-specific antibiotics (OR 0.5). Furthermore, UTI-specific antibiotic use was not associated with urothelial carcinomas (n = 11,029; OR 1.13; CI 0.97-1.32). Excluding patients with known urogenital disease did not influence the SCC estimates (overall OR 10.8; CI 6.2-18.9). Data on smoking were lacking, however, a quantitative bias analysis suggested this to be of limited importance. In conclusion, common UTIs are strong, dose-dependent and specifically associated with risk of SCC of the bladder.

No Decrease in Fracture Risk Despite 15 Years of Treatment Evolution in Multiple Myeloma Patients: A Danish Nationwide Case-Control Study

Introduction Bone lesions are one of the primary symptoms in multiple myeloma (MM), and it has been suggested that these lesions adversely impact overall survival (OS). In the last decades, intensified supportive care and new treatment strategies were introduced to improve overall survival and quality of life. Bortezomib may have the capacity to stimulate bone formation, but reduction in skeletal morbidity has not been demonstrated yet. In addition, data on the fracture risk of MM patients in time are lacking. We hypothesized that the improved treatment strategies and supportive care, including the use of bisphosphonates, reduced the risk of fractures in MM patients at the population level. Therefore, the aim of this study is to determine the effect of different treatment periods on the risk of any fracture in patients with MM. Secondary objectives were to determine the risk of vertebral fractures, and the effects of gender and age on the occurrence of all fractures. Methods A case-control study has been performed using data from the Danish National Health Service. Cases were defined as patients who had sustained a fracture between 1996 and 2011, and controls were those without a fracture. To evaluate the risk of fractures in time, we divided this period in three cohorts: 1996-2000, 2001-2006 and 2007-2011. Vertebral fractures, gender, and age were considered in secondary analyses. Conditional logistic regression was used to estimate odds ratios (ORs) of fracture risk, and the analyses were adjusted for comorbidities and recent drug use. Participants Cases (n = 925,341) were defined as patients who had sustained a fracture between 1996 and 2011, and controls (n = 925,341) were those without a fracture. Exposure was defined as an ICD code for MM. Results Among cases, the risk of any fracture was higher in MM patients compared to patients without MM (Table 1, any fracture: ORadj [95% CI] 1996-2000, 1.7 [1.3 to 2.3]; 2001-2006, 1.3 [1.1 to 1.6]; 2007-2011, 1.7 [1.4 to 2.2]). Although fractures were mainly non-vertebral, the risk of vertebral fractures in particular was higher in MM patients (Table 1, vertebral fracture: ORadj [95% CI] 1996-2000, 3.5 [1.4 to 8.6]; 2001-2006, 4.0 [1.9 to 8.2]; 2007-2011, 3.0 [1.6 to 5.7]). The risk of any fracture was just as high for male as for female MM patients in the three different time cohorts (male: ORadj [95% CI] 1996-2000, 1.8 [1.2 to 2.6]; 2001-2006, 1.6 [1.1 to 2.2]; 2007-2011, 1.9 [1.4 to 2.6], and female: ORadj [95% CI] 1996-2000, 1.6 [1.2 to 2.1]; 2001-2006, 1.1 [0.9 to 1.4]; 2007-2011, 1.6 [1.3 to 2.2]), as well as for patients aged ≤65 or &gt;65 years (≤65 years: ORadj [95% CI] 1996-2000, 1.7 [1.04 to 2.6]; 2001-2006, 1.5 [1.03 to 2.2]; 2007-2011, 2.2 [1.5 to 3.2], and &gt;65 years: ORadj [95% CI] 1996-2000, 1.7 [1.3 to 2.2]; 2001-2006, 1.2 [0.96 to 1.5]; 2007-2011, 1.6 [1.3 to 2.1]). Conclusions Despite new treatment strategies and improved supportive care, this nationwide case-control study showed no decreased fracture risk for MM patients over time. It is thus crucial for physicians to be aware of the ever-elevated fracture risk in MM patients, especially of the vertebrae. Further steps are necessary to reduce fracture risk, and at the same time, to improve the OS of these patients. New treatment strategies, even if they have a positive impact on OS, offer no guarantee for a corresponding reduction in bone lesions. Disclosures Bergh: Sanofi: Membership on an entity's Board of Directors or advisory committees, Other: speakers fee; Eli Lilly: Membership on an entity's Board of Directors or advisory committees, Other: speakers fee; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: speakers fee; UCB: Membership on an entity's Board of Directors or advisory committees, Other: speakers fee.

Risk of Multiple System Atrophy and the Use of Anti-Inflammatory Drugs: A Danish Register-Based Case-Control Study

Introduction: Multiple system atrophy (MSA) is a rare rapidly progressive atypical Parkinson disorder presenting clinically with parkinsonism and/or a cerebellar syndrome in combination with dysautonomia. Severe neuroinflammation develops along with hallmark neuropathological changes, and as in Parkinson’s disease, intake of anti-inflammatory medication has been hypothesized to be protective for development of disease. We aimed to investigate if use of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin, or statins were associated with a reduced risk of MSA. Methods: We performed a register-based case-control study in MSA (n = 155) cases and population controls (n= 7,750) matched on age, gender, and place of residency by risk-set sampling. Pharmacological exposure prior to diagnosis was assessed in 2 categories (user vs. nonuser, cumulated dose in tertiles [T1-T3]). In an unconditional logistic regression model, adjusted for age, gender, residency, and chronic obstructive pulmonary disease (COPD), we estimated ORs and 95% CIs. Results: Data suggested a trend towards non-aspirin NSAID use to be associated with a decreased risk of MSA (OR 0.72 [95% CI 0.49–1.06]) compared to nonusers, decreasing dose-dependently (T2 OR 0.77 [95% CI 0.43–1.38]; T3 OR 0.55 [95% CI 0.29–1.06]). However, data were based on small numbers. Use of statins and low-dose aspirin was not associated with a decreased risk of MSA. Results were lagged 5 years from index date to address reverse causation. Conclusion: A trend toward use of non-aspirin NSAID and an associated reduced risk of MSA was observed in this study. However, our analyses had limited statistical precision, and further studies including larger sample sizes and longer exposure periods are needed.

Use of phthalate-containing prescription drugs and the risk of gastric cancer: a Danish nationwide case-control study

Background: Phthalates are used as excipients in some drug products, and up to a 50-fold increased urinary excretion of phthalate metabolites compared to non-users has been demonstrated in users of such products. In vitro studies have demonstrated that phthalates stimulate mechanisms involved in gastric cancer development. We therefore examined the association between cumulative phthalate exposure from drug products and the risk of gastric adenocarcinomas.Methods: Using the Danish Cancer Registry, we identified all patients with incident gastric adenocarcinoma from 2008 to 2015 (n = 1525). Cancer cases were matched to 10 controls. Linking information retrieved from nationwide Danish registries, we determined individual cumulative phthalate exposure to the ortho-phthalates diethyl phthalate (DEP), dibutyl phthalate (DBP) and enteric phthalate polymers from prescription drugs. The association between cumulative phthalate exposure and gastric adenocarcinoma was estimated using conditional logistic regression, adjusting for socioeconomical status and drugs or comorbidities known or suspected to modify the risk of gastric adenocarcinoma.Results: No association was seen for the risk of gastric adenocarcinomas among individuals with high cumulative exposure to ortho-phthalates (exceeding 500 mg) (ORadj 1.22, 95% CI: 0.84–1.77). Likewise, no associations were observed individually for DEP (ORadj 1.06 95% CI: 0.63–1.76) or DBP (ORadj 1.32 95% CI: 0.78–2.23). Cumulative exposure to enteric phthalate polymers exceeding 10,000 mg, did not reveal an association with gastric adenocarcinoma (ORadj 0.79, 95% CI: 0.54–1.16) and no association was seen for individual compounds. Additionally, no dose-response pattern was observed across exposure strata (p = .39, test for trend).Conclusion: We did not find an increased risk of gastric adenocarcinoma among Danish users of phthalate-containing drug products. Our study is limited by a low number of cases exposed to high cumulative doses of phthalates.

Hospital contacts and diagnoses five years prior to HPV vaccination among females referred for suspected adverse vaccine effects: A Danish nationwide case-control study

BackgroundHigh health care utilization before Human Papilloma Virus (HPV) vaccination might be associated with increased risk of suspected adverse effects (AE’s) after vaccination. We investigated the association between hospital contacts and diagnoses before HPV vaccination and risk of later referral to a specialized hospital setting (HPV center) for suspected AE’s. MethodsThe study was a Danish register-based matched case-control study. Cases were females referred to an HPV center. Five controls per case were randomly selected in the source population of HPV vaccinated females. Information on hospital contacts and diagnoses was obtained from the Danish National Patient Registry. Conditional logistic regression analyses were used to investigate the association between having one or more diagnoses in each specific International Classification of Diseases 10th version (ICD-10) chapter five years before the HPV vaccination and subsequent referral to an HPV center. ResultsWe identified 1496 cases and 7480 controls. In total, 80% of the cases versus 65% of the controls had at least one hospital contact prior to HPV vaccination (Prevalence Proportion Ratio - PPR: 1.24 (95% Confidence Interval - CI: 1.21–1.27)), with 24% vs 12% (PPR: 1.97 (95% CI: 1.76–2.19)) having six or more contacts. Cases were more likely to have had a diagnosis in 15 out of 19 ICD-10 chapters before the vaccination, with ORs larger than 1.8 for infectious diseases, psychiatric diseases, diseases of the nervous, circulatory, digestive and musculoskeletal system, unspecific symptoms and unspecific contacts. ConclusionPre-vaccination morbidity and health care utilization seem to play a role in the path leading to suspected AE’s after HPV vaccination. Since many of the diagnoses that were particularly increased before vaccination in referred females are overlapping with the most frequent symptoms reported, we cannot exclude that for some of the females, the suspected AE’s might have been existing already before the vaccination.