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Assessment of comorbidity is crucial for confounding adjustment and prediction of mortality in register-based studies, but the commonly used Charlson comorbidity index is not sufficiently predictive. We aimed to develop a multidimensional diagnosis-based comorbidity index (MDCI) that captures comorbidity better than the Charlson Comorbidity index. The index was developed based on 286,688 men free of prostate cancer randomly selected from the Swedish general population, and validated in 54,539 men without and 68,357 men with prostate cancer. All ICD-10 codes from inpatient and outpatient discharges during 10 years prior to the index date were used to define variables indicating frequency of code occurrence, recency, and total duration of related hospital admissions. Penalized Cox regression was used to predict 10-year all-cause mortality. The MDCI predicted risk of death better than the Charlson comorbidity index, with a c-index of 0.756 (95% confidence interval [CI] = 0.751, 0.762) vs 0.688 (95% CI = 0.683, 0.693) in the validation cohort of men without prostate cancer. Men in the lowest vs highest MDCI quartile had distinctively different survival in the validation cohort of men with prostate cancer, with an overall hazard ratio [HR] of 5.08 (95% CI = 4.90, 5.26). This was also consistent within strata of age and Charlson comorbidity index, e.g. HR = 5.90 (95% CI = 4.65, 7.50) in men younger than 60 years with CCI 0. These results indicate that comorbidity assessment in register-based studies can be improved by use of all ICD-10 codes and taking related frequency, recency, and duration of hospital admissions into account. [ABSTRACT FROM AUTHOR]

We aimed to estimate the absolute and age-standardized number of hip fractures in Sweden during the past two decades to produce time trends and future projections. We used nationwide register data from 1998 to 2019 and a validated algorithm to calculate the annual absolute and age-standardized number of incident hip fractures over time. The total hip fracture burden was 335,399 incident events over the 22 years, with a change from 16,180 in 1998 to 13,929 in 2019, a 14% decrease. One decade after the index hip fracture event, 80% of the patients had died, and 11% had a new hip fracture. After considering the steady growth of the older population, the decline in the age-standardized number of hip fractures from 1998 through 2019 was 29.2% (95% CI 28.1–30.2%) in women and 29.3% (95% CI 27.5–30.7%) in men. With a continued similar reduction in hip fracture incidence, we can predict that 14,800 hip fractures will occur in 2034 and 12,000 in 2050 despite doubling the oldest old (≥ 80 years). Without an algorithm, a naïve estimate of the total number of hip fractures over the study period was 539,947, with a second 10-year hip fracture risk of 35%. We note an ongoing decline in the absolute and age-standardized actual number of hip fractures in Sweden, with consequences for future projections. [ABSTRACT FROM AUTHOR]

Purpose: Studies of rare side effects of new drugs with limited exposure may require pooling of multiple data sources. Federated Analyses (FA) allow real‐time, interactive, centralized statistical processing of individual‐level data from different data sets without transfer of sensitive personal data. Methods: We review IT‐architecture, legal considerations, and statistical methods in FA, based on a Swedish Medical Products Agency methodological development project. Results: In a review of all post‐authorisation safety studies assessed by the EMA during 2019, 74% (20/27 studies) reported issues with lack of precision in spite of mean study periods of 9.3 years. FA could potentially improve precision in such studies. Depending on the statistical model, the federated approach can generate identical results to a standard analysis. FA may be particularly attractive for repeated collaborative projects where data is regularly updated. There are also important limitations. Detailed agreements between involved parties are strongly recommended to anticipate potential issues and conflicts, document a shared understanding of the project, and fully comply with legal obligations regarding ethics and data protection. FA do not remove the data harmonisation step, which remains essential and often cumbersome. Reliable support for technical integration with the local server architecture and security solutions is required. Common statistical methods are available, but adaptations may be required. Conclusions: Federated Analyses require competent and active involvement of all collaborating parties but have the potential to facilitate collaboration across institutional and national borders and improve the precision of postmarketing drug safety studies. [ABSTRACT FROM AUTHOR]

An inverse association between use of antiepileptic drugs (AEDs) and prostate cancer (PCa) has been suggested, putatively due to the histone deacetylases inhibitory (HDACi) properties of the AEDs. In a case-control study in Prostate Cancer data Base Sweden (PCBaSe), PCa cases diagnosed between 2014 and 2016 were matched to five controls by year of birth and county of residence. AED prescriptions were identified in the Prescribed Drug Registry. Odds ratios (ORs) and 95% confidence intervals for risk of PCa were estimated using multivariable conditional logistic regression, adjusted for civil status, education level, Charlson comorbidity index, number of outpatient visits, and cumulative duration of hospital stay. Dose responses in different PCa risk categories and HDACi properties of specific AED substances were further explored. 1738/31591 (5.5%) cases and 9674/156802 (6.2%) controls had been exposed to AED. Overall, users of any AED had a reduced risk of PCa as compared to nonusers (OR: 0.92; 95% CI: 0.87–0.97) which was attenuated by adjustment to healthcare utilisation. A reduced risk was also observed in all models for high-risk or metastatic PCa in AED users compared to nonusers (OR: 0.89; 95% CI: 0.81–0.97). No significant findings were observed for dose response or HDACi analyses. Our findings suggest a weak inverse association between AED use and PCa risk, which was attenuated by adjustment for healthcare utilisation. Moreover, our study showed no consistent dose-response pattern and no support for a stronger reduction related to HDAC inhibition. Further studies focusing on advanced PCa and PCa treatments are needed to better analyse the association between use of AED and risk of PCa. [ABSTRACT FROM AUTHOR]

Background: Randomised controlled trials have demonstrated prolonged survival with new upfront treatments in addition to standard androgen deprivation therapy (ADT) in men with de novo metastatic castration-sensitive prostate cancer. We describe patient characteristics, time trends and regional differences in uptake of these new treatment strategies in clinical practice. Material and methods: This descriptive study consisted of men registered in the National Prostate Cancer Register of Sweden from 1 January 2018 to 31 March 2022 with de novo metastatic castration-sensitive prostate cancer defined by the presence of metastases on imaging at the time of diagnosis. Life expectancy was calculated based on age, Charlson Comorbidity Index and a Drug Comorbidity Index. Results: Within 6 months from diagnosis, 57% (1,677/2,959) of men with de novo metastatic castration-sensitive prostate cancer and more than 3 years of life expectancy had received docetaxel, abiraterone, enzalutamide, apalutamide and/or radiotherapy. Over time, there was a 2-fold increase in uptake of any added treatment, mainly driven by a 6-fold increase in use of abiraterone, enzalutamide or apalutamide, with little change in use of other treatments. Conclusions: Slightly more than half of men diagnosed with de novo metastatic castration-sensitive prostate cancer and a life expectancy of at least 3 years received additions to standard ADT as recommended by national guidelines in 2019-2022 in Sweden. There was a 2-fold increase in use of these treatments during the study period; however, efforts to further increase adherence to guidelines are warranted. [ABSTRACT FROM AUTHOR]

Background: Coronavirus disease 2019 (COVID-19) mRNA vaccines are associated with an increased risk of myocarditis using hospital discharge diagnoses as an outcome. The validity of these register-based diagnoses is uncertain. Methods: Patient records for subjects < 40 years of age and a diagnosis of myocarditis in the Swedish National Patient Register were manually reviewed. Brighton Collaboration diagnosis criteria for myocarditis were applied based on patient history, clinical examination, laboratory data, electrocardiograms, echocardiography, magnetic resonance imaging and myocardial biopsy. Poisson regression was used to estimate incidence rate ratios, comparing the register-based outcome variable to validated outcomes. Interrater reliability was assessed by a blinded re-evaluation. Results: Overall, 95.6% (327/342) of cases registered as myocarditis were confirmed (definite, probable or possible myocarditis according to Brighton Collaboration diagnosis criteria, positive predictive value 0.96 [95% CI 0.93-0.98]). Of the 4.4% (15/342) cases reclassified as no myocarditis or as insufficient information, two cases had been exposed to the COVID-19 vaccine no more than 28 days before the myocarditis diagnosis, two cases were exposed >28 days before admission and 11 cases were unexposed to the vaccine. The reclassification had only minor impact on incidence rate ratios for myocarditis following COVID-19 vaccination. In total, 51 cases were sampled for a blinded re-evaluation. Of the 30 randomly sampled cases initially classified as either definite or probably myocarditis, none were re-classified after re-evaluation. Of the in all 15 cases initially classified as no myocarditis or insufficient information, 7 were after re-evaluation re-classified as probable or possible myocarditis. This re-classification was mostly due to substantial variability in electrocardiogram interpretation. Conclusion: This validation of register-based diagnoses of myocarditis by manual patient record review confirmed the register diagnosis in 96% of cases and had high interrater reliability. Reclassification had only a minor impact on the incidence rate ratios for myocarditis following COVID-19 vaccination. [ABSTRACT FROM AUTHOR]

Androgen deprivation therapy (ADT) has been hypothesized to protect against COVID‐19, but previous observational studies of men with prostate cancer on ADT have been inconsistent regarding mortality risk from coronavirus disease 2019 (COVID‐19). Using data from the Prostate Cancer data Base Sweden (PCBaSe), we identified a cohort of 114 547 men with prevalent prostate cancer on the start of follow‐up in February 2020, and followed them until 16 December 2020 to evaluate the association between ADT and time to test positive for COVID‐19. Among men testing positive for COVID‐19, we used regression analyses to estimate the association between ADT and risk of COVID‐19‐related hospital admission/death from any cause within 30 days of the positive test. In total, 1695 men with prostate cancer tested positive for COVID‐19. In crude analyses, exposure to ADT was associated with a 3‐fold increased risk of both testing positive for COVID‐19 infection and subsequent hospital admission/death. Adjustment for age, comorbidity and prostate cancer risk category substantially attenuated the associations: HR 1.3 (95% CI: 1.1‐1.5) for testing positive for COVID‐19, and OR 1.4 (95% CI: 1.0‐1.9) for risk of subsequent hospital admission/death. In conclusion, although these results suggest increased risks of a positive COVID‐19 test, and COVID‐19‐related hospital admission/death in men on ADT, these findings are likely explained by confounding by old age, cancer‐associated morbidity and other comorbidities being more prevalent in men on ADT, rather than a direct effect of the therapy. [ABSTRACT FROM AUTHOR]

Background: We aimed to optimize prediction of long-term all-cause mortality of intensive care unit (ICU) patients, using quantitative register-based comorbidity information assessed from hospital discharge diagnoses prior to intensive care treatment.Material and Methods: Adult ICU admissions during 2006 to 2012 in the Swedish intensive care register were followed for at least 4 years. The performance of quantitative comorbidity measures based on the 5-year history of number of hospital admissions, length of stay, and time since latest admission in 36 comorbidity categories was compared in time-to-event analyses with the Charlson comorbidity index (CCI) and the Simplified Acute Physiology Score (SAPS3).Results: During a 7-year period, there were 230,056 ICU admissions and 62,225 deaths among 188,965 unique individuals. The time interval from the most recent hospital stays and total length of stay within each comorbidity category optimized mortality prediction and provided clear separation of risk categories also within strata of age and CCI, with hazard ratios (HRs) comparing lowest to highest quartile ranging from 1.17 (95% CI: 0.52-2.64) to 6.41 (95% CI: 5.19-7.92). Risk separation was also observed within SAPS deciles with HR ranging from 1.07 (95% CI: 0.83-1.38) to 3.58 (95% CI: 2.12-6.03).Conclusion: Baseline comorbidity measures that included the time interval from the most recent hospital stay in 36 different comorbidity categories substantially improved long-term mortality prediction after ICU admission compared to the Charlson index and the SAPS score. Trial registration ClinicalTrials.gov ID NCT04109001, date of registration 2019-09-26 retrospectively. [ABSTRACT FROM AUTHOR]

Androgens facilitate entrance of the severe acute respiratory syndrome coronavirus 2 into respiratory epithelial cells, and male sex is associated with a higher risk of death from corona virus disease (COVID-19). Androgen deprivation therapy (ADT) could possibly improve COVID-19 outcomes. In a case–control study nested in the Prostate Cancer data Base Sweden (PCBaSe) RAPID 2019, we evaluated the association between ADT and COVID-19 as registered cause of death in men with prostate cancer. Each case was matched to 50 controls by region. We used conditional logistic regression to adjust for confounders and also evaluated potential impact of residual confounding. We identified 474 men who died from COVID-19 in March–December 2020. In crude analyses, ADT exposure was associated with an increased risk of COVID-19 death (odds ratio [OR] 5.05, 95% CI: 4.18–6.10); however, the OR was substantially attenuated after adjustment for age, comorbidity, prostate cancer characteristics at diagnosis, recent healthcare use, and indicators of advanced cancer (adjusted OR 1.25, 95% CI: 0.95–1.65). If adjustment has accounted for at least 85% of confounding, then the true effect could be no more than a 5% reduction of the odds for COVID-19 death. The increased mortality from COVID-19 in men with prostate cancer treated with ADT was mainly related to high age, comorbidity, and more advanced prostate cancer. There was no evidence to support the hypothesis that ADT is associated with improved COVID-19 outcomes. [ABSTRACT FROM AUTHOR]

The article informs about time on treatment with abiraterone in men with de novo metastatic castration sensitive prostate cancer. Topics include demonstrated an increased overall survival by addition of the androgen receptor targeted agent abiraterone acetate to gonadotropin-releasing hormone (GnRH) agonist treatment in men; and drug utilization in routine care to detect signals suggesting a potentially different effectiveness in clinical practice.

Introduction: For clinical decision-making, an estimate of remaining lifetime is needed to assess benefit against harm of a treatment during the remaining lifespan. Here, we describe how to predict life expectancy based on age, Charlson Comorbidity Index (CCI) and a Drug Comorbidity Index (DCI), whilst also considering potential future changes in CCI and DCI using population-based data on Swedish men.Methods: Simulations based on annual updates of vital status, CCI and DCI were used to estimate life expectancy at population level. The probabilities of these transitions were determined from generalised linear models using prostate cancer-free comparison men in PCBaSe Sweden. A simulation was performed for each combination of age, CCI, and DCI. Survival curves were created and compared to observed survival. Life expectancy was then calculated as the area under the simulated survival curve.Results: There was good agreement between observed and simulated survival curves for most ages and comorbidities, except for younger men. With increasing age and comorbidity, there was a decrease in life expectancy. Cross-validation based on six regions in Sweden also showed that simulated and observed survival was similar.Conclusion: Our proposed method provides an alternative statistical approach to estimate life expectancy at population level based on age and comorbidity assessed by routinely collected information on diagnoses and filled prescriptions available in nationwide health care registers. [ABSTRACT FROM AUTHOR]

Background: Men have a higher risk of death from COVID-19 than women and androgens facilitate entrance of the SARS-CoV-2 virus into respiratory epithelial cells. Thus, androgen deprivation therapy may reduce infection rates and improve outcomes for COVID-19. In the spring of 2020, Sweden was highly affected by COVID-19. The aim was to estimate the impact of androgen deprivation therapy on mortality from COVID-19 in men with prevalent prostate cancer by comparing all-cause mortality in the spring of 2020 to that in previous years. Patients and methods: Using the Prostate Cancer data Base Sweden all men with prostate cancer on March 1 each year in 2015–2020 were followed until June 30 the same year. Exposure to androgen deprivation therapy was ascertained from filled prescriptions for bicalutamide monotherapy, gonadotropin-releasing hormone agonists (GnRH), or bilateral orchidectomy. Results: A total of 9,822 men died in March-June in the years 2015–2020, of whom 5,034 men were on androgen deprivation therapy. There was an excess mortality in 2020 vs previous years in all men. The crude relative mortality rate ratio for 2020 vs 2015–2019 was 0.93 (95% confidence interval (CI) 0.83 to 1.04) in men on GnRH, and 0.90 (95% CI 0.78 to 1.05) in men on bicalutamide monotherapy. After multivariable adjustment these ratios were attenuated to 1.00 (95% CI 0.89 to 1.12) and 0.97 (95% CI 0.84 to 1.12), respectively. When restricting the analysis to the regions with the highest incidence of COVID-19 or to the time period between 2 April to 10 June when mortality in 2020 was increased >30% compared to previous years, the results were similar to the main analysis. Conclusions: In this large national population-based cohort of men with prevalent prostate cancer, there was no clear evidence in support for an effect of androgen deprivation therapy on COVID-19 mortality. [ABSTRACT FROM AUTHOR]

Background: The Charlson Comorbidity Index is a poor predictor of mortality in men with castration resistant prostate cancer (CRPC). To improve this prediction, we created a comorbidity index based on filled prescriptions intended to be used in registry-based studies. Materials and methods: In a population-based cohort of men with CPRC a drug comorbidity index (DCI-CRPC) was calculated based on prescriptions filled during a 365-day period before the date of CRPC diagnosis to predict mortality. Five risk categories for men with CRPC were defined based on PSA kinetics. Mortality rates were described by Kaplan-Meier curves. The predictive ability of the DCI-CRPC was compared in univariable models to that of the original DCI, derived from men in the general population, and to that of the Charlson Comorbidity Index. Results: In 1,885 men with CRPC the median overall survival ranged from 3.0 years (95% confidence interval [CI] 2.8 to 3.4) in the first tertile of the DCI-CRPC, to 1.0 year (95% CI 0.9 to 1.1) in the third tertile of the DCI-CRPC. The index had higher discriminative ability (C-index 0.667) than the Charlson Comorbidity Index (C-index 0.508). The discriminative ability of the DCI-CRPC was highest in the subgroup with least aggressive cancer (C-index 0.651) and lowest in men with most aggressive cancer (C-index 0.618). The performance of the DCI-CRPC was comparable to that of the original DCI. Conclusion: Our newly created comorbidity index using filled prescriptions predicted death in men with CRPC better than the Charlson Comorbidity Index. [ABSTRACT FROM AUTHOR]

The use of quinolones has recently been questioned due to reports on side effects including an increased risk of aortic aneurysm. The aim of the study was to examine the risk of aortic aneurysm (AA) after short-term ciprofloxacin as prophylaxis for prostate biopsy. We used the Prostate Cancer data Base Sweden and investigated 192,024 prostate biopsy exposures vs. 554,974 non-exposures for risk of AA. Prostate biopsy was used as a proxy for quinolone use as short-term ciprofloxacin is the recommended and documented prophylaxis in Sweden for this procedure. The outcome was the hazard ratio (HR) of AA in men who underwent a biopsy vs. those that did not. The absolute risk of AA was small, 39/10,000 person years for all AÁs and for ruptured AÁs 3.5/10,000 person years. In multivariate analyses, there were small, non-significant increases in risk of all AA's (adjusted HR = 1.13, 95% CI: 0.91 to 1.39) and ruptured AÁs (adjusted HR = 1.05, 95% CI: 0.52 to 2.15) in men who underwent biopsy. A significantly increased risk of AA was observed in men diagnosed with high-risk prostate cancer on biopsy (HR = 1.50, 95% CI: 1.15–2.21). The use of prostate biopsy as a proxy for exposure to ciprofloxacin was a limitation of the study. Short-term ciprofloxacin was not associated with an increased risk of aortic aneurysm and the increased risk in men with high-risk prostate cancer was likely due detection bias caused by imaging more commonly performed in these men. [ABSTRACT FROM AUTHOR]

Men with prostate cancer (PCa) on gonadotropin-releasing hormone agonists (GnRH) have an increased risk of cardiovascular disease (CVD) compared to men with PCa not on GnRH as well as compared with PCa-free men. Whether the addition of androgen receptor targeted (ART) drugs to GnRH further increases CVD risk, remains to be fully elucidated. We investigated risk of CVD for men with castration resistant PCa (CRPC) on GnRH plus ART; abiraterone or enzalutamide vs 5,127 and 12,079 respective matched comparator men on GnRH in Prostate Cancer data Base Sweden (PCBaSeTraject) 4.1 between 1 June 2015 and 31 December 2018. PCBaSeTraject links National Prostate Cancer Register of Sweden to other healthcare registries and demographic databases. We conducted multivariable Cox proportional hazard models adjusting for PCa risk category, Charlson comorbidity index (CCI), insulin or statin use, civil status, level of education, history of CVD events and number of CVD drugs, with any incident or fatal CVD as the outcome. 1,310 men were treated with abiraterone and 3,579 with enzalutamide. In multivariable analysis, CVD risk was increased in men on abiraterone (hazard ratio (HR): 1.19; 95% confidence interval (CI): 1.03–1.38) and in men on enzalutamide (HR: 1.10; 95% CI: 1.01–1.20). Men with a recent CVD (<12 months) including both men on ART as well as comparators had a much higher probability of a new CVD vs men with no prior CVD. CVD risk was mildly increased in men with PCa on GnRH plus abiraterone or enzalutamide vs comparator men on GnRH. Residual confounding and detection bias may at least partly explain this association. [ABSTRACT FROM AUTHOR]

Background: The coronavirus disease 2019 (COVID-19) vaccines have been rapidly implemented in national vaccination programs world-wide after accelerated approval processes. The large population exposure achieved in very short time requires systematic monitoring of safety. The Swedish Medical Products Agency has launched a project platform for epidemiological surveillance to detect and characterise suspected adverse effects of COVID-19 vaccines in Sweden. Methods: The platform includes all individuals 12 years or older in Sweden in 2021 and will be updated annually. Data, including vaccine and COVID-19 disease data, socioeconomic and demographic data, comorbidity, prescribed medicines and healthcare utilisation outcomes, are obtained from several national registers in collaboration with other Swedish Government agencies. Data from 2015 to 2019 are used as a historical comparison cohort unexposed to both the COVID-19 pandemic and to the COVID-19 vaccines. Results: The primary study cohort includes 8,305,978 adults 18 years and older permanently residing in Sweden on 31 December 2020. The historical control cohort includes 8,679,641 subjects. By 31 July 2021, around 50% of those 18 years and older and two-thirds of those 50 years and older were vaccinated with at least one dose, 90% of those 70 years or older had two doses. Conclusions: The nationwide register-based study cohort created by the Swedish Medical Products Agency with regular updates of individual level linkage of COVID-19 vaccination exposure data to other health data registers will facilitate both safety signal detection and evaluation and other pharmacoepidemiological studies. [ABSTRACT FROM AUTHOR]

In the article, the authors discuss their study to assess uptake of the new indication for upfront utilization of abiraterone plus prednisolone with gondadotropin releasing hormone agonist (GnRH) in men with de novo high-risk metastatic hormone sensitive (mHSPC) and castration resistant prostate cancer (CRPC). Also cited are how the Charlson Comorbidity Index (CCI) was calculated, and the use of Sweden's National Prostate Cancer Register (NPCR) data in the study.

Background: Understanding the association between patients' history of prescribed medications and mortality rate could optimize characterization of baseline risk when the Charlson Comorbidity Index is insufficient. Methods: Using a Swedish cohort of men selected randomly as controls to men with prostate cancer diagnosed 2007–2013, we estimated the association between medications prescribed during the previous year and mortality rates, using Cox regression stratified for age. Results: Among the 326,450 older men with median age of 69 years included in this study, 73% were categorized as free of comorbidity according to the Charlson Comorbidity Index; however, 84% had received at least one prescription during the year preceding the follow-up. This was associated with a 60% overall increase in mortality rate (hazard ratio [HR] = 1.60, 95% confidence interval [CI] 1.56 to 1.64). Some drugs that were unexpectedly associated with mortality included locally acting antacids (HR = 4.7, 95% CI 4.4 to 5.1), propulsives (HR = 4.7, 95% CI 4.4 to 5.0), vitamin A and D (HR = 4.6, 95% CI 4.3 to 4.9), and loop diuretics, for example furosemide (HR = 3.7; 95% CI 3.6 to 3.8). Thiazide diuretics, however, were only weakly associated with a mortality risk (HR = 1.5; 95% CI 1.4 to 1.5). Surprisingly, only weak associations with mortality were seen for major cardiovascular drug classes. Conclusions: A majority of older men had a history of prescribed medications and many drug classes were associated with mortality rate, including drug classes not directly indicated for a specific comorbidity represented in commonly used comorbidity measures. Prescription history can improve baseline risk assessment but some associations might be context-sensitive. [ABSTRACT FROM AUTHOR]

Purpose To estimate risk for narcolepsy in defined time windows following exposure to adjuvanted A(H1N1) pandemic vaccine (Pandemrix) and impact of different definitions of index date for the narcolepsy diagnosis. Methods: Vaccine exposure in approximately 30% of the Swedish population in 2009 was linked to information on narcolepsy diagnosis retrieved from the national patient registry. Cases were verified by a systematic chart review. Poisson regression was used to compare incidence in defined time windows following vaccination. Results: Of 266 cases of narcolepsy identified, 25% (66/266) were prevalent cases with symptom onset documented before vaccine exposure. Incident cases had a median time interval between first symptom and the date recorded in the patient registry of 64 weeks (IQR 39‐107) when vaccinated (N = 182) and 65 weeks (IQR 51‐72) when unvaccinated (N = 16). With first symptom defining index date, the adjusted risk for narcolepsy in younger patients was increased 14 times during the first year after vaccination, three times elevated the second year, but with no detectable increased risk more than 2 years after vaccination exposure. Using the index date from the patient registry, the adjusted increase in risk was about seven times elevated for all three time intervals. Conclusions: The magnitude of the estimated increased risk for narcolepsy following exposure to the A(H1N1) pandemic vaccine is highly dependent on the method used to determine the index date for disease onset. The sometimes very long and potentially variable interval from first symptom to a health care registry diagnosis complicates estimations of risk. [ABSTRACT FROM AUTHOR]

Background: Routinely collected laboratory biomarkers could improve control of confounding from disease severity in non-interventional studies of general intensive care unit (ICU) patients. Their ability to predict both short- and long-term mortality was evaluated.Methods: The performance of age, sex, Charlson co-morbidity index, and baseline values of ten predefined blood biomarkers as predictors of 30-day and 1-year mortality was evaluated in 5505 general ICU stays.Results: Regression models based on age, sex, Charlson index, and biomarkers were somewhat less accurate in predicting 30-day mortality (c-index 0.83, Brier score 0.27) compared to the SAPS II score (c-index = 0.88, Brier score = 0.09) and in predicting 1-year mortality (c-index = 0.82, Brier score = 0.31) compared to the SAPS II score (c-index = 0.85, Brier score = 0.13). Cystatin C improved predictive ability slightly compared to creatinine, but age and Charlson comorbidity index were more important predictors. Using multiple imputation to replace missing biomarker values notably improved predictive ability of the models.Conclusions: Automatically collected baseline variables are almost as predictive of both short- and long-term mortality in general ICU patients, as the SAPS II score. This can facilitate internal control of confounding in non-interventional studies of mortality using administrative data. [ABSTRACT FROM AUTHOR]

The pragmatic clinical trial addresses scientific questions in a setting close to routine clinical practice and sometimes using routinely collected data. From a regulatory perspective, when evaluating a new medicine before approving marketing authorization, there will never be enough patients studied in all subgroups that may potentially be at higher risk for adverse outcomes, or sufficient patients to detect rare adverse events, or sufficient follow-up time to detect late adverse events that require long exposure times to develop. It may therefore be relevant that post-marketing trials sometimes have more pragmatic characteristics, if there is a need for further efficacy and safety information. A pragmatic study design may reflect a situation close to clinical practice, but may also have greater potential methodological concerns, e.g. regarding the validity and completeness of data when using routinely collected information from registries and health records, the handling of intercurrent events, and misclassification of outcomes. In a regulatory evaluation it is important to be able to isolate the effect of a specific product or substance, and to have a defined population that the results can be referred to. A study feature such as having a wide and permissive inclusion of patients might therefore actually hamper the utility of the results for regulatory purposes. Randomization in a registry-based setting addresses confounding that could otherwise complicate a corresponding non-interventional design, but not any other methodological issues. Attention to methodological basics can help generate reliable study results, and is more important than labelling studies as 'pragmatic'. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to describe content and procedures in some selected Swedish health care quality registries (QRs) of relevance to regulatory decision-making. Methods: A workshop was organized with participation of seven Swedish QRs which subsequently answered a questionnaire regarding registry content on drug treatments and outcomes. Patient populations, coverage, data handling and quality control, as well as legal and ethical aspects are presented. Scientific publications from the QRs are used as a complementary measure of quality and scientific relevance. Results: The registries under study collect clinical data of high relevance to regulatory and health technology agencies. Five out of seven registries provide information on the drug of interest. When applying external quality criteria, we found a high degree of fulfillment, although information on medication was not sufficient to answer all questions of regulatory interest. A notable strength is the option for linkage to the Prescribed Drug Registry and to information on education and socioeconomic status. Data on drugs used during hospitalization were also collected to some extent. Outcome measures collected resemble those used in relevant clinical trials. All registries collected patient-reported outcome measures. The number of publications from the registries was substantial, with studies of appropriate design, including randomized registry trials. Conclusions: Quality registries may provide a valuable source of post-marketing data on drug effectiveness, safety, and cost-effectiveness. Closer collaboration between registries and regulators to improve quality and usefulness of registry data could benefit both regulatory utility and value for health care providers. [ABSTRACT FROM AUTHOR]

Purpose To estimate the incidence trend and outcome of paracetamol poisoning, in relation to increased availability of paracetamol from non-pharmacy outlets in 2009. Method Patients' serum paracetamol results over 14 years (2000-2013) from 20 (out of 21) regions in Sweden were linked to national registers of hospital care, cause of death, and prescriptions. Paracetamol poisonings were defined by serum paracetamol levels, hospital diagnoses, or cause of death. The change in incidence of poisonings following increased availability of paracetamol was analysed by using segmental regression of time series. Results Of the 12 068 paracetamol poisonings, 85% were classified as intentional self-harm. Following increased availability from non-pharmacy outlets, there was a 40.5% increase in the incidence of paracetamol poisoning, from 11.5/100 000 in 2009 to 16.2/100 000 in 2013. Regression analyses indicated a change in the trend ( p < 0.0001) but not an immediate jump in the incidence ( p = 0.5991) following the increased availability. Adjusting for trends in hospital episodes for self-harm, suicides, and the sales volume of paracetamol did not influence the result. All-cause mortality at 30 days (3.2%) did not change over time. Conclusions The incidence of paracetamol poisoning in Sweden has increased since 2009, contrasting the decreased incidence in the period of 2007-2009. The change in trend was temporally associated with the introduction of availability of paracetamol from non-pharmacy outlets but did not appear to be related to sales volume of paracetamol or general trends in self-harm or suicides. © 2017 Commonwealth of Australia. Pharmacoepidemiology and Drug Safety © 2017 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

FRAX is a tool that identifies individuals with high fracture risk who will benefit from pharmacological treatment of osteoporosis. However, a majority of fractures among elderly occur in people without osteoporosis and most occur after a fall. Our aim was to accurately identify men with a high future risk of fracture, independent of cause. In the population-based Uppsala Longitudinal Study of Adult Men (ULSAM) and using survival analysis we studied different models' prognostic values (R2) for any fracture and hip fracture within 10 years from age 50 ( n = 2322), 60 ( n = 1852), 71 ( n = 1221), and 82 ( n = 526) years. During the total follow-up period from age 50 years, 897 fractures occurred in 585 individuals. Of these, 281 were hip fractures occurring in 189 individuals. The rates of any fracture were 5.7/1000 person-years at risk from age 50 years and 25.9/1000 person-years at risk from age 82 years. Corresponding hip fractures rates were 2.9 and 11.7/1000 person-years at risk. The FRAX model included all variables in FRAX except bone mineral density. The full model combining FRAX variables, comorbidity, medications, and behavioral factors explained 25% to 45% of all fractures and 80% to 92% of hip fractures, depending on age. The corresponding prognostic values of the FRAX model were 7% to 17% for all fractures and 41% to 60% for hip fractures. Net reclassification improvement (NRI) comparing the full model with the FRAX model ranged between 40% and 53% for any fracture and between 40% and 87% for hip fracture. Within the highest quintile of predicted fracture risk with the full model, one-third of the men will have a fracture within 10 years after age 71 years and two-thirds after age 82 years. We conclude that the addition of comorbidity, medication, and behavioral factors to the clinical components of FRAX can substantially improve the ability to identify men at high risk of fracture, especially hip fracture. © 2012 American Society for Bone and Mineral Research. [ABSTRACT FROM AUTHOR]

Objective To assess whether higher mortality rates among individuals in motor vehicle crashes in areas with low population density depend on injury type and severity or are related to the performance of emergency medical services (EMS). Methods Prehospital and hospital deaths were studied in a population-based cohort of 41 243 motor vehicle crashes that occurred in Sweden between 1998 and 2004. The final multivariable analysis was restricted to 6884 individuals in motor vehicle crashes, to minimise the effects of confounding factors. Results Crude mortality rates following motor vehicle crashes were inversely related to regional population density. In regions with low population density, the unadjusted rate ratio for prehospital death was 2.2 (95% CI 1.9 to 2.5) and for hospital death 1.5 (95% CI 1.1 to 1.9), compared with a high-density population. However, after controlling for regional differences in age, gender and the type/severity of injuries among 6884 individuals in motor vehicle crashes, low population density was no longer associated with increased mortality. At 25 years of age, predicted prehospital mortality was 9% lower (95% CI 5% to 12%) in regions with low population density compared with high population density. This difference decreased with increasing age, but was still 3% lower (95% CI 0.5% to 5%) at 65 years of age. Conclusions The inverse relationship between population density and mortality among individuals in motor vehicle crashes is related to pre-crash factors that influence the type and severity of injuries and not to differences in EMS. [ABSTRACT FROM PUBLISHER]

Background: Vitamin D is not only important for bone health but can also affect the development of several non-bone diseases. The definition of vitamin D insufficiency by serum levels of 25-hydroxyvitamin D depends on the clinical outcome but might also be a consequence of analytical methods used for the definition. Although numerous 25-hydroxyvitamin D assays are available, their comparability is uncertain. We therefore aim to investigate the precision, accuracy and clinical consequences of differences in performance between three common commercially available assays. Methodology/Principal Findings: Serum 25-hydroxyvitamin D levels from 204 twins from the Swedish Twin Registry were determined with high-pressure liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry (HPLCAPCI-MS), a radioimmunoassay (RIA) and a chemiluminescent immunoassay (CLIA). High inter-assay disagreement was found. Mean 25-hydroxyvitamin D levels were highest for the HPLC-APCI-MS technique (85 nmol/L, 95% CI 81-89), intermediate for RIA (70 nmol/L, 95% CI 66-74) and lowest with CLIA (60 nmol/L, 95% CI 56-64). Using a 50-nmol/L cut-off, 8% of the subjects were insufficient using HPLC-APCI-MS, 22% with RIA and 43% by CLIA. Because of the heritable component of 25-hydroxyvitamin D status, the accuracy of each method could indirectly be assessed by comparison of within-twin pair correlations. The strongest correlation was found for HPLC-APCI-MS (r = 0.7), intermediate for RIA (r = 0.5) and lowest for CLIA (r = 0.4). Regression analyses between the methods revealed a non-uniform variance (p,0.0001) depending on level of 25-hydroxyvitamin D. Conclusions/Significance: There are substantial inter-assay differences in performance. The most valid method was HPLCAPCI- MS. Calibration between 25-hydroxyvitamin D assays is intricate. [ABSTRACT FROM AUTHOR]

The article presents a study which examined the relation between cardiovascular disease (CVD) and risk of hip fracture in twins and assessed the relative importance of genetics and lifestyle factors in this association. It was found that there was an association between diagnosis of CVD and the risk of subsequent hip fracture. Genetic factors that might explain the associations between CVD and hip fracture are discussed. According to the article, clinicians need to be aware of the increased rate of hip fracture in both men and women, especially after a hospitalization for CVD.

TEN and HUS are challenging complications with excessive mortality after HSCT. We report the development of these two conditions in combination in a nine-yr-old boy after HSCT from an unrelated donor. TEN with skin detachment of more than 90% of body surface area developed after initial treatment for GvHD. Within a few days of admission to the burns unit, the patient developed severe hemolysis, hypertension, thrombocytopenia, and acute renal failure consistent with HUS, apparently caused by CSA. The management included intensive care in a burns unit, accelerated drug removal using plasmapheresis, and a dedicated multi-disciplinary team approach to balance immunosuppression and infections management in a situation with extensive skin detachment. The patient survived and recovered renal function but requires continued treatment for severe GvHD. Suspecting and identifying causative drugs together with meticulous supportive care in the burns unit is essential in the management of these patients and long-term survival is possible. [ABSTRACT FROM AUTHOR]

New risk factors for various diseases are suggested at an increasing pace, with promise of clinical usefulness for risk prediction, but almost unvaryingly without formal testing of that property. We propose that a risk factor clinically relevant for risk prediction can be defined as one that correctly alters predicted risk to a clinically relevant extent in persons with a relevant absolute risk, such that it affects clinical decision making. We recommend that investigators who suggest a new risk factor for clinical use investigate if the new risk factor adds capacity to discriminate between persons who will subsequently experience the outcome from those who will not. For that purpose, we provide tools for calculating the net reclassification improvement, NRI, and the integrated discrimination improvement, IDI, using major statistical packages. [ABSTRACT FROM PUBLISHER]

Background: A female survival advantage after injury has been observed, and animal models of trauma have suggested either hormonal or genetic mechanisms as component causes. Our aim was to compare age and risk-adjusted sex-related mortality in hospital for the three most common mechanisms of injury in relation to hormonal effects as seen by age. Methods: All hospital admissions for injury in Sweden during the period 2001–2011 were retrieved from the National Patient Registry and linked to the Cause of Death Registry. The International Classification of Diseases Injury Severity Score (ICISS) was used to adjust for injury severity, and the Charlson Comorbidity Index to adjust for comorbidity. Age categories (0–14, 15–50, and ≥ 51 years) were used to represent pre-menarche, reproductive and post- menopausal women. Results: Women had overall a survival benefit (OR 0.51; 95% CI 0.50 to 0.53) after adjustment for injury severity and comorbidity. A similar pattern was seen across the age categories (0–14 years OR 0.56 (95% CI 0.25 to 1.25), 15–50 years OR 0.70 (95% CI 0.57 to 0.87), and ≥ 51 years OR 0.49 (95% CI 0.48 to 0.51)). Conclusion: In this 11-year population-based study we found no support for an oestrogen-related mechanism to explain the survival advantage for females compared to males following hospitalisation for injury. [ABSTRACT FROM AUTHOR]

Background: The interpretation of changes in injury-related mortality over time requires an understanding of changes in the incidence of the various types of injury, and adjustment for their severity. Our aim was to investigate changes over time in incidence of hospital admission for injuries caused by falls, traffic incidents, or assaults, and to assess the risk-adjusted short-term mortality for these patients. Methods: All patients admitted to hospital with injuries caused by falls, traffic incidents, or assaults during the years 2001–11 in Sweden were identified from the nationwide population-based Patient Registry. The trend in mortality over time for each cause of injury was adjusted for age, sex, comorbidity and severity of injury as classified from the International Classification of diseases, version 10 Injury Severity Score (ICISS). Results: Both the incidence of fall (689 to 636/100000 inhabitants: p = 0.047, coefficient − 4.71) and traffic related injuries (169 to 123/100000 inhabitants: p < 0.0001, coefficient − 5.37) decreased over time while incidence of assault related injuries remained essentially unchanged during the study period. There was an overall decrease in risk-adjusted 30-day mortality in all three groups (OR 1.00; CI95% 0.99–1.00). Decreases in traffic (OR 0.95; 95% CI 0.93 to 0.97) and assault (OR 0.93; 95% CI 0.87 to 0.99) related injuries was significant whereas falls were not during this 11-year period. Discussion: Risk-adjustment is a good way to use big materials to find epidemiological changes. However after adjusting for age, year, sex and risk we find that a possible factor is left in the pre- and/or in-hospital care. Conclusions: The decrease in risk-adjusted mortality may suggest changes over time in pre- and/or in-hospital care. A non-significantdecrease in risk-adjusted mortality was registered for falls, which may indicate that low-energy trauma has not benefited for the increased survivability as much as high-energy trauma, ie traffic- and assault related injuries. [ABSTRACT FROM AUTHOR]

Presents a letter to the editor about surgical procedures that minimize trauma of feeding tube exchange in patients with bleeding diathesis.

The article presents an abstract of the study related to the dietary calcium intake and risk of fracture and osteoporosis.

Background Classification of injuries and estimation of injury severity on the basis of ICD-10 injury coding are powerful epidemiological tools. Little is known about the characteristics and consequences of primary coding errors and their consequences for such applications. Materials and methods From the Swedish national hospital discharge register, 15 899 incident injury cases primarily admitted to the two hospitals in Uppsala County between 2000 and 2004 were identified. Of these, 967 randomly selected patient records were reviewed. Errors in injury diagnosis were corrected, and the consequences of these changes were analysed. Results Out of 1370 injury codes, 10% were corrected, but 95% of the injury codes were correct to the third position. In 21% (95% CI 19% to 24%) of 967 hospital admissions, at least one ICD-10 code for injury was changed or added, but only 13% (127) had some change made to their injury mortality diagnosis matrix classification. Among the cases with coding errors, the mean ICD-based injury severity score changed slightly (difference 0.016; 95% CI 0.007 to 0.032). The area under the receiver operating characteristics curve was 0.892 for predicting hospital mortality and remained essentially unchanged after the correction of codes (95% CI for difference -0.022 to 0.013). Conclusion Errors in ICD-10-coded injuries in hospital discharge data were common, but the consequences for injury categorisation were moderate and the consequences for injury severity estimates were in most cases minor. The error rate for detailed levels of cause-of-injury codes was high and may be detrimental for identifying specific targets for prevention. [ABSTRACT FROM AUTHOR]

Background Classification of injuries and estimation of injury severity on the basis of ICD-10 injury coding are powerful epidemiological tools. Little is known about the characteristics and consequences of primary coding errors and their consequences for such applications. Materials and methods From the Swedish national hospital discharge register, 15 899 incident injury cases primarily admitted to the two hospitals in Uppsala County between 2000 and 2004 were identified. Of these, 967 randomly selected patient records were reviewed. Errors in injury diagnosis were corrected, and the consequences of these changes were analysed. Results Out of 1370 injury codes, 10% were corrected, but 95% of the injury codes were correct to the third position. In 21% (95% CI 19% to 24%) of 967 hospital admissions, at least one ICD-10 code for injury was changed or added, but only 13% (127) had some change made to their injury mortality diagnosis matrix classification. Among the cases with coding errors, the mean ICD-based injury severity score changed slightly (difference 0.016; 95% CI 0.007 to 0.032). The area under the receiver operating characteristics curve was 0.892 for predicting hospital mortality and remained essentially unchanged after the correction of codes (95% CI for difference -0.022 to 0.013). Conclusion Errors in ICD-10-coded injuries in hospital discharge data were common, but the consequences for injury categorisation were moderate and the consequences for injury severity estimates were in most cases minor. The error rate for detailed levels of cause-of-injury codes was high and may be detrimental for identifying specific targets for prevention. [ABSTRACT FROM AUTHOR]

The article presents research seeking to determine how increased physical activity after middle age influences mortality. The results are compared to effect of smoking cessation. The design and setting of the population based cohort study involving 50 year-old-men from Sweden is described. Research results found that increased physical activity in middle age significantly increased longevity between the ages of 50 and 60 compared to inactivity. Similar mortality reduction was seen after smoking cessation compared to continued smoking.