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UNLABELLED: Osteoporosis in men may be underdiagnosed. One in four men in Denmark will develop osteoporosis after age of 50 years, with fracture as a common presenting symptom.PURPOSE: The aim of this study was to describe epidemiology of male osteoporosis in Denmark.METHODS: In this nationwide registry-based cohort study, we identified men with osteoporosis, 50 years or older, residing in Denmark, during the years 1996-2018. Osteoporosis was defined as one of the following: a hospital diagnosis of osteoporosis; a hospital diagnosis of osteoporosis fracture; or an outpatient dispensing of an anti-osteoporosis medication. We reported annual incidence and prevalence and described the distribution of fractures, comorbidities, socioeconomic status, and initiation of anti-osteoporosis therapy among men with osteoporosis. Selected characteristics were also described among men without osteoporosis of similar age.RESULTS: There were 171,186 men fulfilling the study criteria for osteoporosis. The overall age-standardized incidence rate of osteoporosis was 8.6 per 1000 person-years (95% confidence interval (CI), 8.5-8.6), varying between 7.7 and 9.7, while the prevalence increased from 4.3% (95% CI, 4.2-4.3) to 7.1% (95% CI, 7.0-7.1) during the 22-year period. The remaining-lifetime risk of developing osteoporosis after age of 50 years was close to 30%. The proportion of men initiating anti-osteoporosis treatment within 1 year of diagnosis increased from 6.9% to 29.8%. Men with osteoporosis had more comorbidities and redeemed more medication than did men without osteoporosis of similar age.CONCLUSION: Osteoporosis among men may be undertreated despite increasing treatment initiation.

The availability of electronic health records and access to a large number of routine measurements of serum creatinine and urinary albumin enhance the possibilities for epidemiologic research in kidney disease. However, the frequency of health care use and laboratory testing is determined by health status and indication, imposing certain challenges when identifying patients with kidney injury or disease, when using markers of kidney function as covariates, or when evaluating kidney outcomes. Depending on the specific research question, this may influence the interpretation, generalizability, and/or validity of study results. This review illustrates the heterogeneity of working definitions of kidney disease in the scientific literature and discusses advantages and limitations of the most commonly used approaches using 3 examples. We summarize ways to identify and overcome possible biases and conclude by proposing a framework for reporting definitions of exposures and outcomes in studies of kidney disease using routinely collected health care data.

OBJECTIVES: To assess the risk of benign prostatic hyperplasia (BPH)-related surgery and acute urinary retention (AUR) in men treated with 5-alpha-reductase inhibitor (5-ARI) versus alpha-blocker monotherapy in routine clinical care over 15 years of follow-up.METHODS: Using population-based Danish Health registries, we identified all new-users of 5-ARI or alpha-blocker monotherapy in Denmark, 1997-2017. We defined an index date 180 days after the date of first prescription and included men who redeemed at least one additional prescription before the index date. We used multiple imputation to replace missing prostate-specific antigen values. We performed propensity score-weighted Cox regression to estimate weighted hazard ratios (wHRs) and cumulative incidence function to estimate weighted cumulative risks of BPH-related surgery and AUR in intention to treat (ITT) and per protocol (PP) analyses.RESULTS: We included 18,421 and 95,984 men treated with 5-ARI and alpha-blocker monotherapy, respectively. Overall, treatment with 5-ARI monotherapy was associated with a reduced risk of BPH-related surgery (ITT wHR = 0.73 (95% confidence interval [CI]: 0.68-0.78), PP wHR = 0.77 (95% CI: 0.70-0.84) and AUR (ITT wHR = 0.73 (95% CI: 0.67-0.78), PP wHR = 0.75 (95% CI: 0.66-0.84). The 15-year risk of BPH-related surgery in men treated with 5-ARI versus alpha-blocker monotherapy was 14.8% (95% CI: 14.1%-15.5%) versus 19.1% (95% CI: 18.7%-19.5%) in the ITT analysis and 13.8% (95% CI: 12.6%-14.9%) versus 17.5% (95% CI: 16.9%-18.0%) in the PP analysis. The 15-year risk of AUR in men treated with 5-ARI versus alpha-blocker was 13.0% (95% CI: 12.3%-13.6%) versus 16.6% (95% CI: 16.3%-17.0%) in the ITT analysis and 12.6% (95%: 11.3%-14.0%) versus 16.9% (95% CI: 16.3%-17.6%) in the PP analysis.CONCLUSION: Treatment with 5-ARI versus alpha-blocker monotherapy in routine clinical care was associated with a reduced risk of BPH-related surgery and AUR for up to 15 years of follow-up. After 15 years of follow-up, the relative risk reduction was 21%-25% and the absolute risk reduction was 4%.

OBJECTIVE: To examine trends in incidence of acute urinary retention, subsequent benign prostatic hyperplasia-related treatment and mortality in the era of medical therapy for benign prostatic hyperplasia. Additionally, to compare mortality with the general population.MATERIALS AND METHODS: We conducted a Danish nationwide registry-based study including 70,775 men aged 45 years or older with a first hospitalization for acute urinary retention during 1997-2017. We computed annual standardized incidence rates, subsequent 1-year cumulative incidence of benign prostatic hyperplasia-related surgical and medical treatment, and standardized 3-month and 1-year mortality rates. Finally, we compared standardized all-cause and cause-specific mortality ratios with the general population.RESULTS: The standardized incidence rate of acute urinary retention per 1000 person-years increased transiently from 2.34 to 3.42 during 1997-2004, but gradually declined to 2.95 in 2017. The 1-year cumulative incidence of benign prostatic hyperplasia-related surgery declined from 31.2% to 19.8% and 20.5% to 7.7% after spontaneous and precipitated acute urinary retention, respectively. During 1997-2017, the standardized 1-year mortality declined from 22.2% to 17.2%. Compared with the general population, mortality was 4-5 times higher after 3 months and 2-3 times higher after 1 year of acute urinary retention. The cause-specific standardized mortality ratios were particularly high for deaths attributable to malignancies, urogenital disease, certain infections, chronic pulmonary disease, and diabetes.CONCLUSION: During 1997-2017, we observed a transient increase in the incidence of acute urinary retention. The subsequent use of benign prostatic hyperplasia-related surgery declined considerably and mortality continued to be high, mainly because of deaths from malignancies, urogenital disease, infections, and preexisting comorbidity.

There is substantial variability in the reported incidence and outcomes of acute kidney injury (AKI). The extent to which this is attributable to differences in source populations versus methodological differences between studies is uncertain. We used 4 population-based datasets from Canada, Denmark, and the United Kingdom to measure the annual incidence and prognosis of AKI and acute kidney disease (AKD), using a homogenous analytical approach that incorporated KDIGO creatinine-based definitions and subsets of the AKI/AKD criteria. The cohorts included 7 million adults ≥18 years of age between 2011 and 2014; median age 59-68 years, 51.9-54.4% female sex. Age- and sex-standardised incidence rates for AKI or AKD were similar between regions and years; range 134.3-162.4 events/10,000 person years. Among patients who met either KDIGO 48-hour or 7-day AKI creatinine criteria, the standardised 1-year mortality was similar (30.4%-38.5%) across the cohorts, which was comparable to standardised 1-year mortality among patients who met AKI/AKD criteria using a baseline creatinine within 8-90 days prior (32.0%-37.4%). Standardised 1-year mortality was lower (21.0%-25.5% across cohorts) among patients with AKI/AKD ascertained using a baseline creatinine >90 days prior. These findings illustrate that the incidence and prognosis of AKI and AKD based on KDIGO criteria are consistent across 3 high-income countries when capture of laboratory tests is complete, creatinine-based definitions are implemented consistently within but not beyond a 90-day period, and adjustment is made for population age and sex. These approaches should be consistently applied to improve the generalizability and comparability of AKI research and clinical reporting.

BACKGROUND: The baseline creatinine level is central in the Kidney Disease Improving Global Outcomes (KDIGO) criteria of AKI, but baseline creatinine is often inconsistently defined or unavailable in AKI research. We examined the rate, characteristics, and 30-day mortality of AKI in five AKI cohorts created using different definitions of baseline creatinine.METHODS: This nationwide cohort study included all individuals aged ≥18 years in Denmark with a creatinine measurement in 2017. Applying the KDIGO criteria, we created four AKI cohorts using four different baseline definitions (most recent, mean, or median value of outpatient creatinine 365-368 days before, or median value 90-98 days before, if available, otherwise median value 365-391 days before) and one AKI cohort not using a baseline value. AKI rate and the distribution of age, sex, baseline creatinine, and comorbidity were described for each AKI cohort, and the 30-day all-cause mortality was estimated using the Kaplan-Meier method.RESULTS: The study included 2,095,850 adults with at least one creatinine measurement in 2017. The four different baseline definitions identified between 61,189 and 62,597 AKI episodes. The AKI rate in these four cohorts was 13-14 per 1000 person-years, and 30-day all-cause mortality was 17%-18%. The cohort created without using a baseline creatinine included 37,659 AKI episodes, corresponding to an AKI rate of 8.2 per 1000 person-years and a 30-day mortality of 23%. All five cohorts were similar regarding age, sex, and comorbidity.CONCLUSIONS: In a population-based setting with available outpatient baseline creatinine, different baseline creatinine definitions revealed comparable AKI cohorts, whereas the lack of a baseline creatinine when defining AKI led to a smaller AKI cohort with a higher mortality. These findings underscore the importance of availability and consistent use of an outpatient baseline creatinine, particulary in studies of community-acquired AKI.

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BackgroundAcute kidney injury (AKI) is a common and serious condition defined by a rapid decline in kidney function. Data on changes in long-term kidney function following AKI are sparse and conflicting. Therefore, we examined the changes in estimated glomerular filtration rate (eGFR) from before to after AKI in a nationwide population-based setting.MethodsUsing Danish laboratory databases, we identified individuals with first-time AKI defined by an acute increase in plasma creatinine (pCr) during 2010 to 2017. Individuals with three or more outpatient pCr measurements before and after AKI were included and cohorts were stratified by baseline eGFR (≥/ResultsAmong individuals with a baseline eGFR ≥60 mL/min/1.73 m2 (n = 64 805), first-time AKI was associated with a median difference in eGFR level of −5.6 mL/min/1.73 m2 [interquartile range (IQR) −16.1 to 1.8] and a median difference in eGFR slope of −0.4 mL/min/1.73 m2/year (IQR −5.5 to 4.4). Correspondingly, among individuals with a baseline eGFR ConclusionAmong individuals with first-time AKI surviving to have repeated outpatient pCr measurements, AKI was associated with changes in eGFR level and eGFR slope for which the magnitude and direction depended on baseline eGFR.

BACKGROUND AND OBJECTIVES: Despite CKD consensus definitions, epidemiologic studies use multiple different algorithms to identify CKD. We aimed to elucidate if this affects the patient characteristics and the estimated prevalence and prognosis of CKD by applying six different algorithms to identify CKD in population-based medical databases and compare the cohorts.DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with CKD in Northern Denmark (2009-2016) were identified using six different algorithms: five were laboratory based defined by (1) one measured outpatient eGFR 60 ml/min per 1.73 m2 observed in-between (Kidney Disease Improving Global Outcomes, persistent, n=68,994), (4) two such findings ≥90 and 30 mg/g ≥90 days apart (Kidney Disease Improving Global Outcomes, eGFR/albuminuria, n=100,957). The sixth included patients identified by reported in- and outpatient hospital International Classification of Diseases diagnoses of CKD (hospital-diagnosed, n=27,947). For each cohort, we estimated baseline eGFR, CKD prevalence, and 1-year mortality using the Kaplan-Meier method.RESULTS: The five different laboratory-based algorithms resulted in large differences in the estimated prevalence of CKD from 4637-8327 per 100,000 population. In contrast, 1-year mortality varied only slightly (7%-9%). Baseline eGFR levels at diagnosis were comparable (53-56 ml/min per 1.73 m2), whereas median time since first recorded eGFR CONCLUSIONS: Population prevalence of CKD identified in medical databases greatly depends on the applied algorithm to define CKD. Despite these differences, laboratory-based algorithms produce cohorts with similar prognosis.PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_03_11_CJN15691020_final.mp3.

Aim: The aim of this study was to investigate the association between Parkinson's disease (PD) and postoperative complications, mortality, and quality of in-hospital care in patients with hip fracture. Methods: We included patients aged 65+ years with an incident hip fracture from 2004-2017, registered in the Danish Multidisciplinary Hip Fracture Registry. Patients with PD were identified using diagnosis codes prior to hip fracture. Using log-binomial regression, we calculated both 30-day crude and adjusted risk ratios (aRR) with 95% confidence intervals (CIs) for the following outcomes: any hospital-treated infections, pneumonia, urinary tract infection, sepsis, community-treated infections, cardiovascular events, mortality, and fulfilment of quality indicators of in-hospital care. Analyses were adjusted for age, sex and Charlson comorbidity index score. Results: We identified 77,550 hip fracture patients of which 1,915 had PD. Compared to non-PD, patients with PD had higher risk of any hospital-treated - (aRR = 1.27 (CI: 1.10-1.45) and community-treated infection (aRR = 1.22 (CI: 1.13-1.32)), pneumonia (aRR = 1.38 (1.11-1.69)), urinary tract infection (aRR of 1.58 (CI: 1.28-1.92)) and sepsis (aRR = 1.18 (CI: 0.67-1.89)), but a reduced risk of cardiovascular events (aRR = 0.59 (CI: 0.41-0.82)). The aRR for 30-day mortality was 1.11 (CI: 0.97-1.27) for PD vs non-PD patients, and the aHR for 1-year mortality was 1.19 (CI: 1.09-1.30). The aRRs for fulfillment of all relevant quality indicators was about 1 for PD vs non-PD patients. Conclusion: Hip fracture patients with PD have a higher risk of infections and mortality within 30 days after surgery after adjustment for sex, age, and comorbidity. They do, however, receive comparable quality of in-hospital care after hip fracture compared to non-PD patients.

Objective To develop and validate the DANish Comorbidity index for Acute Myocardial Infarction (DANCAMI) for adjustment of comorbidity burden in studies of myocardial infarction prognosis. Methods Using medical registries, we identified patients with first-time myocardial infarction in Denmark during 2000-2013 (n=36,685). We developed comorbidity indices predicting 1-year all-cause mortality from all comorbidities (DANCAMI) and restricted to non-cardiovascular comorbidities (rDANCAMI). For variable selection, we eliminated comorbidities stepwise using hazard ratios from multivariable Cox models. We compared DANCAMI/rDANCAMI with Charlson and Elixhauser comorbidity indices using standard performance measures (Nagelkerke's R2, Harrell's C-statistic, the Integrated Discrimination Improvement, and the continuous Net Reclassification Index). We assessed the significance of the novel DANCAMI variables not included in the Charlson Comorbidity Index. External validation was performed in patients with myocardial infarction in New Zealand during 2007-2016 (n=75,069). Results The DANCAMI included 24 comorbidities. The rDANCAMI included 17 non-cardiovascular comorbidities. In the Danish cohort, the DANCAMI indices outperformed both the Charlson and the Elixhauser comorbidity indices on all performance measures. The DANCAMI indices included multiple variables that were significant predictors of 1-year mortality even after controlling for all variables in the Charlson Comorbidity Index. These novel variables included valvular heart disease (hazard ratio for 1-year mortality=1.25, 95% CI: 1.14-1.35), coagulopathy (1.13, 95% CI: 1.05-1.22), alcohol and drug abuse (1.35, 95% CI: 1.15-1.58), schizophrenia (1.60, 95% CI: 1.46-1.76), affective disorder (1.29, 95% CI: 1.22-1.36), epilepsy (1.26, 95% CI: 1.05-1.50), neurodegenerative disorder (1.30, 95% CI: 1.10-1.54) and chronic pancreatitis (1.71, 95% CI: 1.14-2.56). The results were supported by the external validation in New Zealand. Conclusion DANCAMI assessed comorbidity burden of patients with first-time myocardial infarction, outperformed existing comorbidity indices, and was generalizable to patients outside Denmark. DANCAMI is recommended as a standard approach for comorbidity adjustment in studies of myocardial infarction prognosis.

Objectives To assess if mammographic density (MD) changes during neoadjuvant breast cancer treatment and is predictive of a pathological complete response (pCR). Methods We prospectively included 200 breast cancer patients assigned to neoadjuvant chemotherapy (NACT) in the NeoDense study (2014–2019). Raw data mammograms were used to assess MD with a fully automated volumetric method and radiologists categorized MD using the Breast Imaging-Reporting and Data System (BI-RADS), 5th Edition. Logistic regression was used to calculate odds ratios (OR) for pCR comparing BI-RADS categories c vs. a, b, and d as well as with a 0.5% change in percent dense volume adjusting for baseline characteristics. Results The overall median age was 53.1 years, and 48% of study participants were premenopausal pre-NACT. A total of 23% (N = 45) of the patients accomplished pCR following NACT. Patients with very dense breasts (BI-RADS d) were more likely to have a positive axillary lymph node status at diagnosis: 89% of the patients with very dense breasts compared to 72% in the entire cohort. A total of 74% of patients decreased their absolute dense volume during NACT. The likelihood of accomplishing pCR following NACT was independent of volumetric MD at diagnosis and change in volumetric MD during treatment. No trend was observed between decreasing density according to BI-RADS and the likelihood of accomplishing pCR following NACT. Conclusions The majority of patients decreased their MD during NACT. We found no evidence of MD as a predictive marker of pCR in the neoadjuvant setting., Highlights • A prospective study of breast cancer patients receiving neoadjuvant chemotherapy. • Study patients with dense breasts often had positive axillary lymph nodes. • Volumetric breast density decreased for most patients after neoadjuvant chemotherapy. • We found no evidence of mammographic density as a predictive marker of pCR.

Purpose Anemia is prevalent in patients with chronic kidney disease (CKD), but the longitudinal risk of anemia in patients with newly identified CKD is unknown. We therefore examined the risks of experiencing anemia in persons with newly identified CKD. Patients and Methods This cohort study included adult patients with newly identified CKD stages 3-5 defined by an estimated glomerular filtration rate (eGFR) level

Purpose To examine the association between statin use and risk of breast cancer recurrence in a national Danish cohort of postmenopausal breast cancer patients receiving aromatase inhibitors (AI) in the adjuvant setting. Patients and methods We enrolled all postmenopausal patients diagnosed with stage I–III estrogen receptor positive breast cancer during the years 2007–2017, assigned adjuvant AI treatment, and registered in both the Danish Breast Cancer Group database and the Danish Cancer Registry. We ascertained incident statin exposure (≥ 1 prescription post-diagnosis) from the Danish National Prescription Registry and modeled statins as a time-varying exposure lagged by 6 months. Follow-up began 7 months after diagnosis and continued to the first event of recurrence, death, emigration, 5 years elapsed, or 25th September 2018. We estimated incidence rates of recurrence at 5 years and used Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CI), comparing statin exposure with non-exposure. Results We enrolled 14,773 eligible patients. During the 5 years of follow-up, there were 32 recurrences in 3163 person-years of follow-up among statin-exposed patients, and 612 recurrences in 45,655 person-years among unexposed patients (incidence rate per 1000 person-years: 10.12 [95% CI 6.92–14.28] and 13.40 [95% CI 12.36–14.51], respectively). In multivariable models, any statin exposure was associated with a reduced rate of 5-year breast cancer recurrence (adjusted HR 0.72 [95% CI 0.50–1.04]). Considering only lipophilic statins as exposure the results were similar (adjusted HR 0.70 [95% CI 0.48–1.02]). Conclusions Statin use was associated with a reduced risk of breast cancer recurrence among postmenopausal patients diagnosed with early stage breast cancer who received adjuvant AI therapy.

Background This study aimed to identify the cumulative incidence and risk factors of metachronous peritoneal metastasis (M‐PM) from colorectal cancer in patients who had intended curative treatment. Methods Patients with colorectal cancer were identified using the Danish Colorectal Cancer Group database for 2006–2015. The Danish Pathology Registry and the Danish National Patient Registry were used to identify M‐PM to 2017. Risk factors were estimated by multivariable absolute risk regression, treating death and other cancers as competing risks. Overall risk and risk differences (RDs) were estimated at 1, 3 and 5 years. Results In 22 586 patients with colorectal cancer, the overall risk of M‐PM was reported to be 0·9 (95 per cent c.i. 0·8 to 1·0) per cent at 1 year, 1·9 (1·8 to 2·1) per cent at 3 years and 2·2 (2·0 to 2·4) per cent at 5 years. Advanced tumour category ((y)pT4 versus (y)pT1) increased the RD of both M‐PM (2·9 (95 per cent c.i. 2·1 to 3·7) at 1 year and 6·0 (4·9 to 7·2) at 3 years) and lymph node involvement ((y)pN2 versus (y)pN0) (2·5 (1·8 to 3·2) at year and 4·3 (3·2 to 5·3) at 3 years). No further increase in risk was observed at 5 years. In a subanalysis, tumour‐involved resection margin (R1 versus R0) was associated with M‐PM with a RD of 3·9 (1·6 to 6·2) at 1 year and 5·9 (2·6 to 9·3) at 3 years. Conclusion The overall risk of M‐PM in patients with colorectal cancer is low, but is increased in advanced T and N status. Follow‐up of at least 3 years after colorectal cancer surgery may be necessary, given the potential curative treatment of early diagnosed M‐PM., In a register‐based study of 22 586 Danish patients with colorectal cancer who had intended curative surgery, a low incidence of metachronous peritoneal metastasis (M‐PM) was found. Risk factors for M‐PM were advanced T and N status and right‐sided colonic tumour. Tumour‐involved resection margins and extramural venous invasion were also associated with M‐PM. Peritoneal metastases and colorectal tumor

INTRODUCTION: The Danish Comorbidity Index for Acute Myocardial Infarction (DANCAMI) was developed to predict one-year mortality after myocardial infarction. We validated DANCAMI in predicting one-year mortality after venous thromboembolism (VTE).MATERIALS AND METHODS: We identified all first-time VTE patients in Denmark during 2000-2015. Using Cox regression, we assessed the performance of DANCAMI to predict one-year all-cause mortality using Nagelkerke's R 2, Harrell's C-Statistic, the net reclassification index (NRI), and the integrated discrimination improvement (IDI). We compared the performance of DANCAMI with the Charlson Comorbidity Index (CCI) and the Elixhauser Comorbidity Index (ECI) and evaluated whether DANCAMI comorbidities not included in the CCI predicted one-year mortality. We stratified the analyses by type (deep vein thrombosis [DVT] and pulmonary embolism [PE]) and presence of provoking risk factors. RESULTS: We identified 108,824 VTE patients of whom 20,649 (19%) died within one year. The R 2, C-Statistic, NRI, and IDI for DANCAMI were 0.35, 0.76, 0.63, and 0.098 for VTE overall; 0.43, 0.80, 0.70, and 0.105 for DVT; and 0.24, 0.71, 0.54, and 0.083 for PE. The R 2 and C-Statistic for VTE overall were 0.35 and 0.76 for CCI and 0.33 and 0.75 for ECI. After adjusting for age, sex, and all CCI comorbidities, seven DANCAMI comorbidities, not included in the CCI, predicted increased mortality. DANCAMI performed better than the CCI and ECI in predicting mortality after provoked VTE, including provoked DVT and PE. CONCLUSION: DANCAMI performed comparable to existing comorbidity indices in predicting one-year mortality after first-time VTE overall, but better after provoked VTE.

Background: In 2019, ranitidine was withdrawn due to high levels of N-nitrosodimethylamine, a probable human carcinogen. The risk of bladder and kidney cancer in ranitidine users, however, remains unclear. Methods: In a Danish nationwide cohort study, we included adults (18 years or older) without previous cancer, who between 1996 and 2008 redeemed at least two prescriptions for ranitidine and, as two separate comparison cohorts, patients with at least two prescriptions for other H2-receptor antagonists (H2-blockers), or proton pump inhibitors (PPI). Follow-up for bladder or kidney cancer started at date of the second prescription and continued to date of cancer, death, emigration, or December 31, 2018, whichever occurred first. We used propensity scores for ranitidine use to compute stabilized inverse probability of treatment (sIPT) weights and used Cox regression to compute crude and weighted HRs. Results: We identified 31,393 initiators of ranitidine, 65,384 initiating other H2-blockers, and 509,849 initiating PPI. Compared with other H2-blockers, the crude HR for bladder cancer was 1.33 [95% confidence interval (CI): 1.15–1.55], but sIPT weighting attenuated this to 1.11 (95% CI: 0.95–1.29). Compared with PPI initiators, the weighted HR was 1.24 (95% CI: 1.04–1.48). For kidney cancer, the weighted HR was 0.89 (95% CI: 0.72–1.10) compared with users of H2-blockers and 0.87 (95% CI: 0.67–1.13) compared with users of PPI. Conclusions: Our findings did not suggest a substantial increase in bladder or kidney cancer occurrence in ranitidine users. Impact: These findings are reassuring for previous ranitidine users.

Background: The discovery that ranitidine is contaminated with N-nitrosodimethylamine, a suspected human carcinogen, raises the hypothesis of a gastrointestinal carcinogenic effect; however, evidence remains inconclusive. Methods: We used the nationwide Danish Prescription Registry to identify a cohort of incident ranitidine users and two active comparator cohorts comprising users of other histamine-2 receptor blockers (H2RB) and users of proton pump inhibitors (PPI). All Danish adults with a first prescription of ranitidine, other H2RBs, or PPIs in 1996 through 2008 were followed virtually completely through 2018 for incidence of esophageal, stomach, liver, and pancreatic cancers. We used Cox regression with propensity-score weighting to calculate hazard ratios and 10-year cumulative risk with 95% confidence intervals. Results: We ascertained 276 newly diagnosed esophageal, 342 stomach, 133 hepatocellular, and 517 pancreatic cancers among ranitidine users during follow-up (median 14 years). In comparison with use of other H2RBs or PPIs, we found no consistent evidence of increased HRs or excess 10-year cumulative risk of any upper gastrointestinal cancer following ranitidine use. We observed no association after restriction to subjects with at least 5 or 10 prescriptions or those with 10 prescriptions and at least 10 years of follow-up. Conclusions: Our large prospective study using high-quality prescription and cancer incidence data, with two active comparator groups, provides no compelling evidence that ranitidine increases the risk of upper gastrointestinal cancers. Impact: Our results, which do not support any carcinogenic effect on esophagus, stomach, liver or pancreas, should be reassuring for millions of concerned past users of ranitidine.

Background: Patients with atrial fibrillation generally require anticoagulant therapy and, at times, therapy with additional platelet aggregation inhibitors. Data are scarce on bleeding rates in high-risk groups receiving combination therapy, such as the elderly or patients with a high CHA 2 DS 2 -VASc score. Methods: We conducted a nationwide cohort study of Danish patients with atrial fibrillation ≥50 years of age. Treatments were ascertained from a prescription database. These included no anticoagulant treatment, and treatment with vitamin K antagonists, direct oral anticoagulants, platelet inhibitors, and combinations of antithrombotic drugs. Incidence rates (IRs) of major bleeding and hazard ratios were estimated overall, and also stratified by treatment modality, age, CHA 2 DS 2 -VASc score, and comorbidity. Major bleeding was defined as bleeding requiring hospitalization or causing death. Results: We identified 272 315 patients with atrial fibrillation. Median age was 75 years (interquartile range, 67–83) and 47% were women. Over a total follow-up period of 1 373 131 patient-years (PYs), 31 459 major bleeds occurred (IR 2.3/100 PYs; 95% CI, 2.3–2.3/100 PYs). In comparison with vitamin K antagonist monotherapy, adjusted hazard ratios of major bleeding were 1.13 (95% CI, 1.06–1.19) for dual antiplatelet therapy, 1.82 (95% CI, 1.76–1.89) for therapy with a vitamin K antagonist and an antiplatelet drug, 1.28 (95% CI, 1.13–1.44) for therapy of a direct oral anticoagulant with an antiplatelet drug, 3.73 (95% CI, 3.23–4.31) for vitamin K antagonist triple therapy, and 2.28 (95% CI, 1.67–3.12) for direct oral anticoagulant triple therapy. Subgroup analyses showed similar patterns. The IR for major bleeding was 10.2/100 PYs among patients receiving triple therapy. Very high major bleeding rates occurred among patients on triple therapy aged >90 years (IR 22.8/100 PYs) or with a CHA 2 DS 2 -VASc score >6 (IR 17.6/100 PYs) or with a history of major bleeding (IR 17.5/100 PYs). Conclusions: Patients with atrial fibrillation on triple therapy experienced high rates of major bleeding in comparison with patients on dual therapy or monotherapy. The high bleeding rates observed in patients on triple therapy >90 years of age or with a CHA 2 DS 2 -VASc score >6 or with a history of a major bleeding warrants careful consideration of such therapy in these patients.

Purpose Personalized cancer treatment requires predictive biomarkers, including image-based biomarkers. Breast cancer (BC) patients receiving neoadjuvant chemotherapy (NACT) are in a clinically vulnerable situation with the tumor present. This study investigated whether mammographic density (MD), assessed pre-NACT, is predictive of pathological complete response (pCR). Methods A total of 495 BC patients receiving NACT in Sweden 2005–2019 were included, merged from two different cohorts. Cohort 1 was retrospectively collected (n = 295) and cohort 2 was prospectively collected (n = 200). Mammograms were scored for MD pre-NACT according to the Breast Imaging-Reporting and Data System (BI-RADS), 5th Edition. The association between MD and accomplishing pCR post-NACT was analyzed using logistic regression models—for the whole cohort, stratified by menopausal status, and in different St. Gallen surrogate subtypes. Results In comparison to patients with low MD (BI-RADS a), the multivariable-adjusted odds ratio (OR) of accomplishing pCR following NACT was on a descending scale: 0.62 (95% confidence interval (CI) 0.24–1.57), 0.38 (95% CI 0.14–1.02), and 0.32 (95% CI 0.09–1.08) for BI-RADS b, c, and d, respectively. For premenopausal patients selectively, the corresponding point estimates were lower, although wider CIs: 0.31 (95% CI 0.06–1.62), 0.24 (95% CI 0.04–1.27), and 0.13 (95% CI 0.02–0.88). Subgroup analyses based on BC subtypes resulted in imprecise estimates, i.e., wide CIs. Conclusions It seemed as though patients with higher MD at baseline were less likely to reach pCR after NACT—a finding more pronounced in premenopausal women. Larger multicenter studies are needed to enable analyses and interpretation for different BC subtypes.

Aims Patients with diabetes and no obstructive coronary artery disease (CAD) as assessed by coronary angiography (CAG) are frequently treated with aspirin and statins. We examined the effectiveness of aspirin and statin treatment on cardiovascular and bleeding incidence in patients with diabetes and absent obstructive CAD. Methods and results The study included patients with diabetes and absent obstructive CAD as assessed by CAG from 2003 to 2016 in Western Denmark. We stratified patients by aspirin and statin treatment within 6 months after CAG in two separate analyses. Outcomes were MACE (major adverse cardiovascular events, a composite of myocardial infarction, ischaemic stroke, and death) and bleeding (aspirin only). To account for confounding, we used propensity score-based weights to estimate the inverse probability of treatment-weighted hazard ratios (HRIPTW). We included 4124 patients with diabetes but without CAD as assessed by CAG, among whom 2474 (60%) received aspirin and 2916 (71%) received statin treatment within 6 months following CAG. Median follow-up was 4.9 years. Aspirin did not reduce 10-year MACE [21.3% vs. 21.8%, HRIPTW 1.01, 95% confidence interval (CI) 0.82–1.25], all-cause death (HRIPTW 0.96, 95% CI 0.74–1.23), or bleeding (HRIPTW 0.95, 95% CI 0.73–1.23), compared to those not receiving aspirin treatment. Statin treatment reduced MACE (25% vs. 37%, HRIPTW 0.58, 95% CI 0.48–0.70) compared to those not receiving statin treatment. Conclusion Among patients with diabetes and no obstructive CAD, aspirin neither reduced MACE nor increased bleeding. In contrast, statin treatment was associated with a major reduction in risk of MACE.

BACKGROUND: Osteonecrosis of the jaw (ONJ) is an adverse effect of antiresorptive treatment. This study estimated incidence proportions and incidence rates of ONJ in cancer patients with bone metastases from solid tumors treated for the prevention of skeletal-related events in routine clinical practice. METHODS: This cohort study in Denmark, Norway, and Sweden in 2011-2018 included 3 treatment cohorts: a denosumab inception cohort (DEIC), a zoledronic acid inception cohort (ZAIC), and a denosumab-switch cohort (DESC). The authors estimated 1- to 5-year incidence proportions and incidence rates of ONJ overall, by cancer site (breast, prostate, or other solid tumor), and by country. ONJ diagnoses were confirmed by adjudication. RESULTS: There were 1340 patients in the DEIC, 1352 in the ZAIC, and 408 in the DESC. The median ages of the 3 cohorts were 70, 69, and 70 years, respectively; the proportions of men were 72.6%, 53.8%, and 48.3%, respectively; and the median follow-up was 19.8, 12.9, and 13.3 months, respectively. The 5-year incidence proportions of ONJ were 5.7% (95% confidence interval [CI], 4.4%-7.3%) in the DEIC, 1.4% (95% CI, 0.8%-2.3%) in the ZAIC, and 6.6% (95% CI, 4.2%-10.0%) in the DESC. The corresponding ONJ incidence rates per 100 person-years were 3.0 (95% CI, 2.3-3.7), 1.0 (95% CI, 0.6-1.5), and 4.3 (95% CI, 2.8-6.3). Incidence proportions and incidence rates were highest in patients with prostate cancer and in Denmark. CONCLUSIONS: This study provides estimates of the risk of medically confirmed ONJ among patients initiating denosumab or zoledronic acid in routine clinical practice in 3 Scandinavian countries. The results varied by cancer site and by country. LAY SUMMARY: Denosumab and zoledronic acid reduce the risk of bone fractures, pain, and surgery in patients with advanced cancers involving bone. Osteonecrosis of the jaw (ONJ)—death of a jawbone—is a known side effect of treatment with denosumab or zoledronic acid. The authors examined almost 2900 denosumab- or zoledronic acid–treated patients with cancer in Denmark, Norway, and Sweden. Over the course of 5 years, ONJ developed in 5.7% of the patients whose initial treatment was denosumab, in 1.4% of the patients whose initial treatment was zoledronic acid, and in 6.6% of the patients who switched from zoledronic acid to denosumab.

ObjectiveTo examine the impact of ACE inhibitor (ACE-I)/angiotensin receptor blocker (ARB) use on rate of SARS-CoV-2 infection and adverse outcomes.MethodsThis nationwide case-control and cohort study included all individuals in Denmark tested for SARS-CoV-2 RNA with PCR from 27 February 2020 to 26 July 2020. We estimated confounder-adjusted ORs for a positive test among all SARS-CoV-2 tested, and inverse probability of treatment weighted 30-day risk and risk ratios (RRs) of hospitalisation, intensive care unit (ICU) admission and mortality comparing current ACE-I/ARB use with calcium channel blocker (CCB) use and with non-use.ResultsThe study included 13 501 SARS-CoV-2 PCR-positive and 1 088 695 PCR-negative individuals. Users of ACE-I/ARB had a marginally increased rate of a positive PCR when compared with CCB users (aOR 1.17, 95% CI 1.00 to 1.37), but not when compared with non-users (aOR 1.00 95% CI 0.92 to 1.09).Among PCR-positive individuals, 1466 (11%) were ACE-I/ARB users. The weighted risk of hospitalisation was 36.5% in ACE-I/ARB users and 43.3% in CCB users (RR 0.84, 95% CI 0.70 to 1.02). The risk of ICU admission was 6.3% in ACE-I/ARB users and 5.4% in CCB users (RR 1.17, 95% CI 0.64 to 2.16), while the 30-day mortality was 12.3% in ACE-I/ARB users and 13.9% in CCB users (RR 0.89, 95% CI 0.61 to 1.30). The associations were similar when ACE-I/ARB users were compared with non-users.ConclusionsACE-I/ARB use was associated neither with a consistently increased rate nor with adverse outcomes of SARS-CoV-2 infection. Our findings support the current recommendation of continuing use of ACE-Is/ARBs during the SARS-CoV-2 pandemic.Trial registration numberEUPAS34887

Background Angiotensin‐converting enzyme inhibitors (ACE‐Is) and angiotensin receptor blockers (ARBs) may worsen the prognosis of coronavirus disease 2019, but any association could be confounded by the cardiometabolic conditions indicating ACE‐I/ARB use. We therefore examined the impact of ACE‐Is/ARBs on respiratory tract infection outcomes. Methods and Results This cohort study included all adult patients hospitalized with influenza or pneumonia from 2005 to 2018 in Denmark using population‐based medical databases. Thirty‐day mortality and risk of admission to the intensive care unit in ACE‐Is/ARBs users was compared with nonusers and with users of calcium channel blockers. We used propensity scores to handle confounding and computed propensity score‐weighted risks, risk differences (RDs), and risk ratios (RRs). Of 568 019 patients hospitalized with influenza or pneumonia, 100 278 were ACE‐I/ARB users and 37 961 were users of calcium channel blockers. In propensity score‐weighted analyses, ACE‐I/ARB users had marginally lower 30‐day mortality than users of calcium channel blockers (13.9% versus 14.5%; RD, −0.6%; 95% CI, −1.0 to −0.1; RR, 0.96; 95% CI, 0.93–0.99), and a lower risk of admission to the intensive care unit (8.0% versus 9.6%; RD, −1.6%; 95% CI, −2.0 to −1.2; RR, 0.83; 95% CI, 0.80–0.87). Compared with nonusers, current ACE‐I/ARB users had lower mortality (RD, −2.4%; 95% CI, −2.8 to −2.0; RR, 0.85; 95% CI, 0.83–0.87), but similar risk of admission to the intensive care unit (RD, 0.4%; 95% CI, 0.0–0.7; RR, 1.04; 95% CI, 1.00–1.09). Conclusions Among patients with influenza or pneumonia, ACE‐I/ARB users had no increased risk of admission to the intensive care unit and slightly reduced mortality after controlling for confounding.

Background Routine clinical evidence is limited on clinical outcomes associated with anemia in patients with severe chronic kidney disease (CKD). Methods We linked population-based medical databases to identify individuals with severe CKD (eGFR 2) in Northern Denmark from 2000 to 2016, including prevalent patients as of 1 January 2009 or incident patients hereafter into the study. We classified patients as non-anemic (≥ 12/≥ 13 g/dl hemoglobin (Hgb) in women/men), anemia grade 1 (10–12/13 g/dl Hgb in women/men), 2 (8–10 g/dl Hgb), and 3+ ( Results We identified 16,972 CKD patients contributing with a total of 28,510 anemia patient profiles, of which 3594 had dialysis dependent (DD) and 24,916 had non-dialysis dependent (NDD) severe CKD. Overall, 14% had no anemia, 35% grade 1 anemia, 44% grade 2 anemia and 17% grade 3+ anemia. Compared to patients with no anemia, adjusted hazard ratios (HRs) for NDD patients with grade 3+ anemia were elevated for incident dialysis (1.91, 95% CI 1.61–2.26), any acute hospitalization (1.74, 95% CI 1.57–1.93), all-cause death (1.82, 95% CI 1.70–1.94), and MACE (1.14, 95% CI 1.02–1.26). Similar HRs were observed among DD patients. Conclusions Among NDD or DD patients with severe CKD, presence and severity of anemia were associated with increased risks of incident dialysis for NDD patients and with acute hospitalizations, death and MACE for all patients.

BACKGROUND: We aimed to examine the association between acute pancreatitis, a potential early symptom of pancreatic cancer, and pancreatic cancer stage, treatment, and prognosis.METHODS: We conducted a cohort study of patients diagnosed with pancreatic cancer during 2004-2017 using population-based registry data from Denmark and Surveillance, Epidemiology, and End Results (SEER) data linked with Medicare claims from the United States (US), which include individuals aged 65 + . We ascertained information on acute pancreatitis diagnoses up to 90 days before pancreatic cancer and followed them for a maximum of five years. We assessed overall survival difference at 30 days, six months, and one, three and five years, comparing patients with and without coexistence of acute pancreatitis. Secondary outcomes were cancer stage and treatment.RESULTS: We identified 12,522 Danish and 37,552 US patients with pancreatic cancer (median age 71 and 78 years, respectively). In the Danish cohort, 1.4 % had acute pancreatitis before pancreatic cancer vs. 5.9 % in the US cohort. After five years of follow-up, the survival difference was 6.1 % (95 % CI: [-0.4 %, 12.6 %]) in Danish and 1.7 % (95 % CI: [0.8 %, 2.7 %]) in US patients, comparing patients with and without acute pancreatitis. Patients with acute pancreatitis had lower prevalence of metastatic tumors at diagnosis (Denmark: 42.5 % vs. 48.7 %; US: 34.4 % vs. 45.9 %) and higher resection frequencies (Denmark: 20.1 % vs. 12.1 %; US: 16.1 % vs.11.3 %) than patients without acute pancreatitis.CONCLUSIONS: Pancreatic cancer patients with acute pancreatitis diagnosed up to 90 days before cancer diagnosis had earlier stage at diagnosis and better survival than patients without acute pancreatitis.

Osteonecrosis of the jaw (ONJ) is an adverse effect of bone‐targeted therapies, which are used to prevent symptomatic skeletal events following bone malignancy. We examined the association between ONJ and survival among cancer patients treated with bone‐targeted agents. Using nationwide registries and databases in Denmark, we identified 184 cancer patients with incident ONJ between 2010 and 2015, and a comparison cohort of 1067 cancer patients without ONJ and with a history of hospital‐administered treatment with bisphosphonates or denosumab initiating from cancer diagnosis. At the date of confirmed ONJ diagnosis, the comparison cohort was matched to the ONJ patients on age, cancer site, year of cancer diagnosis, and stage at diagnosis. The patients were followed up for survival until emigration or 15 June 2016. We computed overall survival and estimated mortality rate ratios adjusted for sex, and for the presence of distant metastases and other comorbidity at start of follow‐up. A match was found for 149 of the 184 ONJ patients. The 1‐ and 3‐year survival among all 184 cancer patients with ONJ was 70% (95% confidence interval [CI]: 63%–76%) and 42% (95% CI: 34%–51%), respectively. Among the matched patients, ONJ was associated with an adjusted mortality rate ratio of 1.31 (95% CI: 1.01–1.71). ONJ was associated with reduced survival among cancer patients treated with bone‐targeted agents. ONJ may be a marker of advanced disease or of survival‐related lifestyle characteristics.

BACKGROUND: To identify demographic characteristics, comorbidities, medical procedures, and prescription drug use that may act as predictors of underlying pancreatic cancer in acute pancreatitis.METHODS: A cohort study of all patients admitted to Danish hospitals with incident acute pancreatitis during 1999-2015. The ability of age, sex, selected comorbidities, medical procedures, and prescription drug use to predict underlying pancreatic cancer in acute pancreatitis (i.e., pancreatic cancer diagnosed up to one year after acute pancreatitis) was examined. The absolute risk and odds ratio (OR) with 95% confidence interval (CI) of cancer was computed for each variable.RESULTS: 28,231 patients with incident acute pancreatitis, of which 283 (1.0%) had underlying pancreatic cancer, were included. Age >50 years was a predictor of pancreatic cancer with highest risk in patients aged 56-70 years. New-onset chronic pancreatitis (multivariable OR: 2.36 [95% CI: 1.35-4.14]) and new-onset diabetes (multivariable OR: 1.94 [95% CI: 1.30-2.92]) were also predictors of pancreatic cancer. Diagnoses of biliary or alcohol-related diseases were predictors of no underlying pancreatic cancer. Most variables examined had no or limited predictive ability.CONCLUSION: Age, new-onset chronic pancreatitis, new-onset diabetes, and absence of biliary or alcohol-related diseases were predictors of underlying pancreatic cancer in acute pancreatitis patients.

Importance Head-to-head randomized clinical trials showed greater efficacy of denosumab vs alendronate in improving bone mineral density. Although there is an association of changes in bone mineral density with reductions in fracture risk, the magnitude of the association is not well established. Objective To compare the risk of hip and any fracture in patients treated with denosumab and alendronate in routine practice settings. Design, Setting, and Participants This Danish nationwide, population-based, historical cohort study of a population with universal access to health care used prospectively collected, individually linked data from Danish health registries with complete follow-up. Cohorts consisted of 92 355 individuals 50 years or older who were new users of denosumab (n = 4624) or alendronate (n = 87 731) from May 2010 to December 2017 after at least 1 year without an antiosteoporosis medication dispensing. Exposures Initiation of denosumab or alendronate. Main Outcomes and Measures The primary outcome was hospitalization for hip fracture, and the secondary outcome was hospitalization for any fracture. Inverse probability of treatment weights and the intention-to-treat approach were used to calculate cumulative incidences and adjusted hazard ratios (aHRs) with 95% CIs. Results Of the 92 355 included patients, 75 046 (81.3%) were women, and the mean (SD) age was 71 (10) years. The denosumab cohort had a lower proportion of men than the alendronate cohort (12.7% [589] vs 19.0% [16 700]), while age distributions were similar in the 2 cohorts. Within 3 years of follow-up, initiation of denosumab or alendronate was associated with cumulative incidences of 3.7% and 3.1%, respectively, for hip fracture and 9.0% and 9.0%, respectively, for any fracture. Overall, the aHRs for denosumab vs alendronate were 1.08 (95% CI, 0.92-1.28) for hip fracture and 0.92 (95% CI, 0.83-1.02) for any fracture. The aHR of denosumab vs alendronate for hip fracture was 1.07 (95% CI, 0.85-1.34) among patients with a history of any fracture and 1.05 (95% CI, 0.83-1.32) among patients without history of fracture. The aHR for any fracture for denosumab vs alendronate was 0.84 (95% CI, 0.71-0.98) among patients with a history of any fracture and 0.77 (95% CI, 0.64-0.93) among patients with no history of fracture. Conclusions and Relevance Treatment with denosumab and alendronate was associated with similar risks of hip or any fracture over a 3-year period, regardless of fracture history.

Key Points Question Is the receipt of α1–adrenergic receptor blocking agents (α1-blockers) associated with protective benefits against adverse outcomes, such as mortality and intensive care unit admission, among adult patients with severe respiratory tract infections? Findings In this cohort study of 528 467 Danish adults hospitalized with influenza or pneumonia, current receipt of α1-blockers was associated with a 14% reduction in the relative risk of 30-day mortality. Meaning This study’s findings suggest that the receipt of α1-blockers may have a clinically relevant association with protective benefits against adverse outcomes among patients with severe respiratory tract infections., Importance Alpha 1–adrenergic receptor blocking agents (α1-blockers) have been reported to have protective benefits against hyperinflammation and cytokine storm syndrome, conditions that are associated with mortality in patients with coronavirus disease 2019 and other severe respiratory tract infections. However, studies of the association of α1-blockers with outcomes among human participants with respiratory tract infections are scarce. Objective To examine the association between the receipt of α1-blockers and outcomes among adult patients hospitalized with influenza or pneumonia. Design, Setting, and Participants This population-based cohort study used data from Danish national registries to identify individuals 40 years and older who were hospitalized with influenza or pneumonia between January 1, 2005, and November 30, 2018, with follow-up through December 31, 2018. In the main analyses, patients currently receiving α1-blockers were compared with those not receiving α1-blockers (defined as patients with no prescription for an α1-blocker filled within 365 days before the index date) and those currently receiving 5α-reductase inhibitors. Propensity scores were used to address confounding factors and to compute weighted risks, absolute risk differences, and risk ratios. Data were analyzed from April 21 to December 21, 2020. Exposures Current receipt of α1-blockers compared with nonreceipt of α1-blockers and with current receipt of 5α-reductase inhibitors. Main Outcomes and Measures Death within 30 days of hospital admission and risk of intensive care unit (ICU) admission. Results A total of 528 467 adult patients (median age, 75.0 years; interquartile range, 64.4-83.6 years; 273 005 men [51.7%]) were hospitalized with influenza or pneumonia in Denmark between 2005 and 2018. Of those, 21 772 patients (4.1%) were currently receiving α1-blockers compared with a population of 22 117 patients not receiving α1-blockers who were weighted to the propensity score distribution of those receiving α1-blockers. In the propensity score–weighted analyses, patients receiving α1-blockers had lower 30-day mortality (15.9%) compared with patients not receiving α1-blockers (18.5%), with a corresponding risk difference of −2.7% (95% CI, −3.2% to −2.2%) and a risk ratio (RR) of 0.85 (95% CI, 0.83-0.88). The risk of ICU admission was 7.3% among patients receiving α1-blockers and 7.7% among those not receiving α1-blockers (risk difference, −0.4% [95% CI, −0.8% to 0%]; RR, 0.95 [95% CI, 0.90-1.00]). A comparison between 18 280 male patients currently receiving α1-blockers and 18 228 propensity score–weighted male patients currently receiving 5α-reductase inhibitors indicated that those receiving α1-blockers had lower 30-day mortality (risk difference, −2.0% [95% CI, −3.4% to −0.6%]; RR, 0.89 [95% CI, 0.82-0.96]) and a similar risk of ICU admission (risk difference, −0.3% [95% CI, −1.4% to 0.7%]; RR, 0.96 [95% CI, 0.83-1.10]). Conclusions and Relevance This cohort study’s findings suggest that the receipt of α1-blockers is associated with protective benefits among adult patients hospitalized with influenza or pneumonia., This cohort study uses data from national registries to examine the association between the receipt of α1–adrenergic receptor blockers and the risks of 30-day mortality and intensive care unit admission among adult patients hospitalized with influenza or pneumonia in Denmark between 2005 and 2018.

Survival among patients with metastatic breast cancer may vary according to the site of metastasis and receptor status. We used Danish nationwide medical registries to establish a cohort of patients with metastatic breast cancer (870 with de novo metastatic disease and 3518 with recurrent disease with distant metastasis) diagnosed during 1997-2011. We examined 1-year and >1 to 5-year mortality associated with first site of metastasis and receptor expression status of the primary tumor. Cox proportional regression was used to compute confounder-adjusted mortality rate ratios (MRRs) associated with site of metastasis, stratified by receptor status. Overall 1-year and >1 to 5-year mortality risks were 36 and 69 %, respectively. Risk of death within 1 year was highest for brain-only (62 %) and liver-only (43 %) involvement and nearly the same for patients with lung-only (32 %), bone-only (32 %) involvement, and other/combination of sites (34 %). Using bone-only metastasis as reference, women with brain-only metastasis had more than two-fold increased risk of dying. The adjusted MRR for women with liver-only metastasis also was increased, though less pronounced. Patients with lung-only [adjusted MRR 0.9 (95 % confidence interval (CI) 0.8, 1.1)] or other metastases [adjusted MRR 1.0 (95 % CI 0.9, 1.2)] had similar mortality as patients with bone-only metastasis. Positive hormonal receptor status was a favorable prognostic factor. Metastatic breast cancer has a serious prognosis. Patients with brain-only metastasis had the highest mortality. Positive hormonal receptor status on the primary tumor was a favorable prognostic factor for all metastatic sites.

Background & Aims Acute pancreatitis may be a risk factor for pancreatic cancer; however, findings from studies on this association are conflicting. We investigated the association between acute pancreatitis and increased risk of pancreatic cancer. Methods We conducted a nationwide, population-based, matched cohort study of all patients admitted to a hospital in Denmark with a diagnosis of acute pancreatitis from January 1, 1980, through October 31, 2012. As many as 5 individuals from the general population without acute pancreatitis were matched for age and sex to each patient with acute pancreatitis. Pancreatic cancer risk was expressed as hazard ratios (HRs) with 95% confidence intervals (CIs), calculated using the Cox proportional hazards model. Cox models were stratified by age, sex, and year of pancreatitis diagnosis and adjusted for alcohol- and smoking-related conditions, and Charlson Comorbidity Index score. Results We included 41,669 patients diagnosed with incident acute pancreatitis and 208,340 comparison individuals. Patients with acute pancreatitis had an increased risk of pancreatic cancer compared with the age- and sex-matched general population throughout the follow-up period. The risk decreased over time but remained high after more than 5 years of follow-up (adjusted HR 2.02; 95% CI 1.57–2.61). Two- and 5-year absolute risks of pancreatic cancer among patients with acute pancreatitis were 0.70% (95% CI 0.62%–0.78%) and 0.87% (95% CI 0.78%–0.97), respectively. Conclusions In a nationwide, population-based, matched cohort study, we observed an association between a diagnosis of acute pancreatitis and long-term risk of pancreatic cancer.

Uffe Heide-Jørgensen, Kasper Adelborg, Johnny Kahlert, Henrik Toft Sørensen, Lars Pedersen Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark Background: For a patient cohort, access to linkable population-based registries permits sampling of a comparison cohort from the general population, thereby contributing to the understanding of the disease in a population context. However, sampling without replacement in random order can lead to immortal time bias by conditioning on the future.Aim: We compared the following strategies for sampling comparison cohorts in matched cohort studies with respect to time to ischemic stroke and mortality: sampling without replacement in random order; sampling with replacement; and sampling without replacement in chronological order.Methods: We constructed index cohorts of individuals from the Danish general population with no particular trait, except being alive and without ischemic stroke on the index date. We also constructed index cohorts of persons aged >50 years from the general population. We then applied the sampling strategies to sample comparison cohorts (5:1 or 1:1) from the Danish general population and compared outcome risks between the index and comparison cohorts. Finally, we sampled comparison cohorts for a heart failure cohort using each strategy.Results: We observed increased outcome risks in comparison cohorts sampled 5:1 without replacement in random order compared to the index cohorts. However, these increases were minuscule unless index persons were aged >50 years. In this setting, sampling without replacement in chronological order failed to sample a sufficient number of comparators, and the mortality risks in these comparison cohorts were lower than in the index cohorts. Sampling 1:1 showed no systematic difference between comparison and index cohorts. When we sampled comparison cohorts for the heart failure patients, we observed a pattern similar to when index persons were aged >50 years.Conclusion: When index persons were aged >50 years, ie, had high outcome risks, sampling 5:1 without replacement introduced bias. Sampling with replacement or 1:1 did not introduce bias. Keywords: matched cohort study, survival analysis, population-based registry, observational study

BACKGROUND Opioids may alter immune function, thereby potentially affecting cancer recurrence. The authors investigated the association between postdiagnosis opioid use and breast cancer recurrence. METHODS Patients with incident, early stage breast cancer who were diagnosed during 1996 through 2008 in Denmark were identified from the Danish Breast Cancer Cooperative Group Registry. Opioid prescriptions were ascertained from the Danish National Prescription Registry. Follow-up began on the date of primary surgery for breast cancer and continued until breast cancer recurrence, death, emigration, 10 years, or July 31, 2013, whichever occurred first. Cox regression models were used to compute hazard ratios and 95% confidence intervals associating breast cancer recurrence with opioid prescription use overall and by opioid type and strength, immunosuppressive effect, chronic use (≥6 months of continuous exposure), and cumulative morphine-equivalent dose, adjusting for confounders. RESULTS In total, 34,188 patients were identified who, together, contributed 283,666 person-years of follow-up. There was no association between ever-use of opioids and breast cancer recurrence (crude hazard ratio, 0.98; 95% confidence interval, 0.90-1.1; adjusted hazard ratio, 1.0; 95% confidence interval, 0.92-1.1), regardless of opioid type, strength, chronicity of use, or cumulative dose. Breast cancer recurrence rates were lower among users of strongly (but not weakly) immunosuppressive opioids, possibly because of channeling bias among those with a high competing risk, because mortality was higher among users of this drug type. CONCLUSIONS This large, prospective cohort study provided no clinically relevant evidence of an association between opioid prescriptions and breast cancer recurrence. The current findings are important to cancer survivorship, because opioids are frequently used to manage pain associated with comorbid conditions. Cancer 2015;121:3435–43. © 2015 American Cancer Society.

ObjectiveWe aimed to investigate the impact of hyponatremia severity on mortality risk and assess any evidence of a dose–response relation, utilizing prospectively collected data from population-based registries.DesignCohort study of 279 508 first-time acute admissions to Departments of Internal Medicine in the North and Central Denmark Regions from 2006 to 2011.MethodsWe used the Kaplan–Meier method (1 – survival function) to compute 30-day and 1-year mortality in patients with normonatremia and categories of increasing hyponatremia severity. Relative risks (RRs) with 95% CIs, adjusted for age, gender and previous morbidities, and stratified by clinical subgroups were estimated by the pseudo-value approach. The probability of death was estimated treating serum sodium as a continuous variable.ResultsThe prevalence of admission hyponatremia was 15% (41 803 patients). Thirty-day mortality was 3.6% in normonatremic patients compared to 7.3, 10.0, 10.4 and 9.6% in patients with serum sodium levels of 130–134.9, 125–129.9, 120–124.9 and ConclusionsHyponatremia is highly prevalent among patients admitted to Departments of Internal Medicine and is associated with increased 30-day and 1-year mortality risk, regardless of underlying disease. This risk seems independent of hyponatremia severity.

OBJECTIVE: To verify the role of proton pump inhibitors (PPI) and nitrofurantoin, which have appeared as novel risk factors for carriage of extended-spectrum beta-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 previous studies.METHODS: Population-based case-control study including 339 cases with community-onset ESBL E. coli UTI in 2007-2012, 3,390 non-ESBL E. coli UTI controls, and 3,390 population controls. We investigated potential risk factors by estimating odds ratios (ORs) and 95% confidence intervals (CIs) adjusting for sex, age, and comorbidity.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 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: prior hospitalization with 1-2 and >2 hospitalizations vs. 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.