Fast tipping point sensitivity analyses in clinical trials with missing continuous outcomes under multiple imputation.

When dealing with missing data in clinical trials, it is often convenient to work under simplifying assumptions, such as missing at random (MAR), and follow up with sensitivity analyses to address unverifiable missing data assumptions. One such sensitivity analysis, routinely requested by regulatory agencies, is the so-called tipping point analysis, in which the treatment effect is re-evaluated after adding a successively more extreme shift parameter to the predicted values among subjects with missing data. If the shift parameter needed to overturn the conclusion is so extreme that it is considered clinically implausible, then this indicates robustness to missing data assumptions. Tipping point analyses are frequently used in the context of continuous outcome data under multiple imputation. While simple to implement, computation can be cumbersome in the two-way setting where both comparator and active arms are shifted, essentially requiring the evaluation of a two-dimensional grid of models. We describe a computationally efficient approach to performing two-way tipping point analysis in the setting of continuous outcome data with multiple imputation. We show how geometric properties can lead to further simplification when exploring the impact of missing data. Lastly, we propose a novel extension to a multi-way setting which yields simple and general sufficient conditions for robustness to missing data assumptions.

An indirect treatment comparison of the efficacy of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg.

AIM: To compare the effects of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg on HbA1c and body weight in patients with type 2 diabetes. MATERIALS AND METHODS: A Bucher indirect comparison was conducted to compare efficacy outcomes of semaglutide 1.0 mg versus dulaglutide 3.0 and 4.5 mg using published results from the SUSTAIN 7 and AWARD-11 trials. Sensitivity analyses using individual patient data from SUSTAIN 7 and aggregate data from AWARD-11 were conducted to explore the impact of adjustment for cross-trial imbalances in baseline characteristics. RESULTS: Semaglutide 1.0 mg significantly reduced HbA1c versus dulaglutide 3.0 mg, with an estimated treatment difference (ETD) of -0.24%-points (95% confidence interval [CI] -0.43, -0.05), with comparable reductions in HbA1c versus dulaglutide 4.5 mg with an ETD of -0.07%-points (95% CI -0.26, 0.12). Semaglutide 1.0 mg significantly reduced body weight versus dulaglutide 3.0 and 4.5 mg with an ETD of -2.65 kg (95% CI -3.57, -1.73) and -1.95 kg (95% CI -2.87, -1.03), respectively. Sensitivity analyses supported the primary analysis findings. CONCLUSIONS: This indirect comparison showed significantly greater reductions in HbA1c with semaglutide 1.0 mg versus dulaglutide 3.0 mg and comparable HbA1c reductions versus dulaglutide 4.5 mg. Semaglutide 1.0 mg significantly reduced body weight versus both dulaglutide 3.0 and 4.5 mg. With several glucagon-like peptide-1 receptor agonists available, information regarding their comparative efficacy can be valuable to clinicians.

White Matter Hyperintensities Improve Ischemic Stroke Recurrence Prediction.

BACKGROUND: Nearly one in 5 patients with ischemic stroke will invariably experience a second stroke within 5 years. Stroke risk stratification schemes based solely on clinical variables perform only modestly in non-atrial fibrillation (AF) patients and improvement of these schemes will enhance their clinical utility. Cerebral white matter hyperintensities are associated with an increased risk of incident ischemic stroke in the general population, whereas their association with the risk of ischemic stroke recurrence is more ambiguous. In a non-AF stroke cohort, we investigated the association between cerebral white matter hyperintensities and the risk of recurrent ischemic stroke, and we evaluated the predictive performance of the CHA2DS2VASc score and the Essen Stroke Risk Score (clinical scores) when augmented with information on white matter hyperintensities. METHODS: In a registry-based, observational cohort study, we included 832 patients (mean age 59.6 (SD 13.9); 42.0% females) with incident ischemic stroke and no AF. We assessed the severity of white matter hyperintensities using MRI. Hazard ratios stratified by the white matter hyperintensities score and adjusted for the components of the CHA2DS2VASc score were calculated based on the Cox proportional hazards analysis. Recalibrated clinical scores were calculated by adding one point to the score for the presence of moderate to severe white matter hyperintensities. The discriminatory performance of the scores was assessed with the C-statistic. RESULTS: White matter hyperintensities were significantly associated with the risk of recurrent ischemic stroke after adjusting for clinical risk factors. The hazard ratios ranged from 1.65 (95% CI 0.70-3.86) for mild changes to 5.28 (95% CI 1.98-14.07) for the most severe changes. C-statistics for the prediction of recurrent ischemic stroke were 0.59 (95% CI 0.51-0.65) for the CHA2DS2VASc score and 0.60 (95% CI 0.53-0.68) for the Essen Stroke Risk Score. The recalibrated clinical scores showed improved C-statistics: the recalibrated CHA2DS2VASc score 0.62 (95% CI 0.54-0.70; p = 0.024) and the recalibrated Essen Stroke Risk Score 0.63 (95% CI 0.56-0.71; p = 0.031). C-statistics of the white matter hyperintensities score were 0.62 (95% CI 0.52-0.68) to 0.65 (95% CI 0.58-0.73). CONCLUSIONS: An increasing burden of white matter hyperintensities was independently associated with recurrent ischemic stroke in a cohort of non-AF ischemic stroke patients. Recalibration of the CHA2DS2VASc score and the Essen Stroke Risk Score with one point for the presence of moderate to severe white matter hyperintensities led to improved discriminatory performance in ischemic stroke recurrence prediction. Risk scores based on white matter hyperintensities alone were at least as accurate as the established clinical risk scores in the prediction of ischemic stroke recurrence.

Death and thrombo-embolic risk after ablation of atrial flutter compared with atrial fibrillation: a nationwide cohort study.

AIMS: The aim of this study was to investigate whether there is a similar mortality and thrombo-embolic risk, after an atrial ablation procedure, compared with an atrial fibrillation (AF) procedure. METHODS AND RESULTS: Using data from nationwide Danish health registries, we identified patients aged 18-75 years undergoing a first-time atrial flutter or an AF ablation procedure in the period 2000-13. Cox proportional hazards regression was used to calculate hazard ratios (HRs) after 5 years of follow-up, adjusting for concomitant risk factors. A total of 1096 and 2266 patients underwent an ablation for atrial flutter or AF, respectively. Age distribution was similar in the two, but atrial flutter patients had more co-morbidities. During 5 years of follow-up, we observed 38 and 36 deaths in the atrial flutter and AF groups, corresponding to an almost two-fold higher mortality rate among atrial flutter patients [crude HR 1.92, 95% confidence interval (CI) 1.22-3.03]. The higher mortality rate persisted after adjustment for age, sex, diabetes mellitus, and hypertension (adjusted HR 1.68, 95% CI 1.05-2.69). The rate of thrombo-embolic events was similar in the two groups (crude HR 1.34, 95% CI 0.71-2.56; adjusted HR 1.22, 95% CI 0.62-2.41). CONCLUSION: In this observational study, patients with atrial flutter had a significantly higher all-cause mortality rate compared with those with AF after an ablation procedure, but similar thrombo-embolic event rates. Future studies should elucidate the reason for this difference in mortality.

Restarting Anticoagulant Treatment After Intracranial Hemorrhage in Patients With Atrial Fibrillation and the Impact on Recurrent Stroke, Mortality, and Bleeding: A Nationwide Cohort Study.

BACKGROUND: Intracranial hemorrhage is the most feared complication of oral anticoagulant treatment. The optimal treatment option for patients with atrial fibrillation who survive an intracranial hemorrhage remains unknown. We hypothesized that restarting oral anticoagulant treatment was associated with a lower risk of stroke and mortality in comparison with not restarting. METHODS AND RESULTS: Linkage of 3 Danish nationwide registries in the period between 1997 and 2013 identified patients with atrial fibrillation on oral anticoagulant treatment with incident intracranial hemorrhage. Patients were stratified by treatment regimens (no treatment, oral anticoagulant treatment, or antiplatelet therapy) after the intracranial hemorrhage. Event rates were assessed 6 weeks after hospital discharge and compared with Cox proportional hazard models. In 1752 patients (1 year of follow-up), the rate of ischemic stroke/systemic embolism and all-cause mortality (per 100 person-years) for patients treated with oral anticoagulants was 13.6, in comparison with 27.3 for nontreated patients and 25.7 for patients receiving antiplatelet therapy. The rate of ischemic stroke/systemic embolism and all-cause mortality (per 100 person-years) for recurrent intracranial hemorrhage, the rate of ischemic stroke/systemic embolism, and all-cause mortality (per 100 person-years) patients treated with oral anticoagulants was 8.0, in comparison with 8.6 for nontreated patients and 5.3 for patients receiving antiplatelet therapy. The adjusted hazard ratio of ischemic stroke/systemic embolism and all-cause mortality was 0.55 (95% confidence interval, 0.39-0.78) in patients on oral anticoagulant treatment in comparison with no treatment. For ischemic stroke/systemic embolism and for all-cause mortality, hazard ratios were 0.59 (95% confidence interval, 0.33-1.03) and 0.55 (95% confidence interval, 0.37-0.82), respectively. CONCLUSIONS: Oral anticoagulant treatment was associated with a significant reduction in ischemic stroke/all-cause mortality rates, supporting oral anticoagulant treatment reintroduction after intracranial hemorrhage as feasible. Future trials are encouraged to guide clinical practice in these patients.

Rivaroxaban versus warfarin and dabigatran in atrial fibrillation: comparative effectiveness and safety in Danish routine care.

PURPOSE: To evaluate effectiveness and safety of rivaroxaban versus warfarin or dabigatran etexilate in a prospective cohort of routine care non-valvular atrial fibrillation (AF) patients during February 2012 to August 2014. METHODS: We identified in nationwide health registries a cohort of AF patients who were new-users of rivaroxaban 15 mg (R15) or 20 mg (R20); dabigatran 110 mg (D110) or 150 mg (D150); or warfarin. Propensity-adjusted Cox regression was used to compare outcome rates in four settings: 'R15 vs. warfarin'; 'R15 vs. D110'; 'R20 vs. warfarin'; and 'R20 vs. D150'. RESULTS: Rivaroxaban users (R15: n = 776; R20: n = 1629) were older and with more comorbidities than warfarin (n = 11 045) and dabigatran users (D110: n = 3588; D150: n = 5320). Rivaroxaban 15-mg users had the overall highest crude mortality rate. After propensity adjustment, rivaroxaban had lower stroke rates vs. warfarin (R15: hazard ratio [HR] 0.46, 95% confidence interval [CI]: 0.26-0.82; R20 HR: 0.72, 95%CI: 0.51-1.01), and similar stroke rates vs. dabigatran. The bleeding rate was similar to warfarin and moderately higher vs. dabigatran (R15 vs. D110 HR: 1.28, 95%CI: 0.82-2.01; R20 vs. D150 HR: 1.81, 95%CI: 1.25-2.62). The mortality rate was higher vs. dabigatran (R15 vs. D110 HR: 1.43, 95%CI: 1.13-1.81; R20 vs. D150 HR: 1.52, 95%CI: 1.06-2.19). CONCLUSIONS: Rivaroxaban was associated with similar or lower stroke rates, but higher bleeding and mortality rates. Channeling of rivaroxaban towards elderly and less healthy patients may have generated residual confounding. In particular, our findings cannot stand alone when deciding which oral anticoagulant to prescribe. Copyright © 2016 John Wiley & Sons, Ltd.

Recurrent Stroke: The Value of the CHA2DS2VASc Score and the Essen Stroke Risk Score in a Nationwide Stroke Cohort.

BACKGROUND AND PURPOSE: The CHA2DS2VASc score and the Essen Stroke Risk Score are respectively used for risk stratification in patients with atrial fibrillation and in patients with cerebrovascular incidents. We aimed to test the ability of the 2 scores to predict stroke recurrence, death, and cardiovascular events (stroke, transient ischemic attack, myocardial infarction, or arterial thromboembolism) in a nationwide Danish cohort study, among patients with incident ischemic stroke and no atrial fibrillation. METHODS: We conducted a registry-based study in patients with incident ischemic stroke and no atrial fibrillation. Patients were stratified according to the CHA2DS2VASc score and the Essen Stroke Risk Score and were followed up until stroke recurrence or death. We estimated stratified incidence rates and hazard ratios and calculated the cumulative risks. RESULTS: 42 182 patients with incident ischemic stroke with median age 70.1 years were included. The overall 1-year incidence rates of recurrent stroke, death, and cardiovascular events were 3.6%, 10.5%, and 6.7%, respectively. The incidence rates, the hazard ratios, and the cumulative risk of all outcomes increased with increasing risk scores. C-statistics for both risk scores were around 0.55 for 1-year stroke recurrence and cardiovascular events and correspondingly for death around 0.67 for both scores. CONCLUSIONS: In this cohort of non-atrial fibrillation patients with incident ischemic stroke, increasing CHA2DS2VASc score and Essen Stroke Risk Score was associated with increasing risk of recurrent stroke, death, and cardiovascular events. Their discriminatory performance was modest and further refinements are required for clinical application.

Female sex is associated with a lower risk of stroke in patients with heart failure.

BACKGROUND: Stroke in patients with heart failure is associated with poor outcomes. Risk stratification schemes may improve clinical decision making in this patient population. This study investigated whether female sex is a risk factor for stroke in patients with heart failure in sinus rhythm. METHODS: This is a population-based cohort study of patients diagnosed with heart failure during 2000 to 2012, identified by record linkage between nationwide Danish registries. Our primary outcome was stroke, and secondary outcome was thromboembolic event. We used relative risks (RRs) after 1 and 5 years to compare males with females within each of the following age groups: 50 to 59 years, 60 to 69 years, 70 to 79 years, 80 to 89 years, and 90+ years. Analyses took into account the competing risks of death. RESULTS: During the study period, 84,142 patients were diagnosed with heart failure, of which 39,946 (47.5%) were females. At 5-year follow-up, female sex was associated with a lower risk of stroke compared with males (adjusted overall hazard ratio 0.91, 95% CI 0.85-0.96). The observed lower risks of stroke in females were not present in the older age groups, where the competing risk of death was substantial among males in particular. When considering a more broadly defined thromboembolic end point, a decreased risk among females persisted across nearly all age groups after 5-year follow-up (adjusted overall hazard ratio 0.93, 95% CI 0.91-0.96). CONCLUSIONS: We found an association between female sex and decreased stroke risk in patients with heart failure, which persisted after adjustment for concomitant cardiovascular risk factors. The association was attenuated with increasing age, possibly because of competing risks of death.

Assessment of the CHA2DS2-VASc Score in Predicting Ischemic Stroke, Thromboembolism, and Death in Patients With Heart Failure With and Without Atrial Fibrillation.

IMPORTANCE: The CHA2DS2-VASc score (congestive heart failure, hypertension, age ≥75 years [doubled], diabetes, stroke/transient ischemic attack/thromboembolism [doubled], vascular disease [prior myocardial infarction, peripheral artery disease, or aortic plaque], age 65-75 years, sex category [female]) is used clinically for stroke risk stratification in atrial fibrillation (AF). Its usefulness in a population of patients with heart failure (HF) is unclear. OBJECTIVE: To investigate whether CHA2DS2-VASc predicts ischemic stroke, thromboembolism, and death in a cohort of patients with HF with and without AF. DESIGN, SETTING, AND POPULATION: Nationwide prospective cohort study using Danish registries, including 42 987 patients (21.9% with concomitant AF) not receiving anticoagulation who were diagnosed as having incident HF during 2000-2012. End of follow-up was December 31, 2012. EXPOSURES: Levels of the CHA2DS2-VASc score (based on 10 possible points, with higher scores indicating higher risk), stratified by concomitant AF at baseline. Analyses took into account the competing risk of death. MAIN OUTCOMES AND MEASURES: Ischemic stroke, thromboembolism, and death within 1 year after HF diagnosis. RESULTS: In patients without AF, the risks of ischemic stroke, thromboembolism, and death were 3.1% (n = 977), 9.9% (n = 3187), and 21.8% (n = 6956), respectively; risks were greater with increasing CHA2DS2-VASc scores as follows, for scores of 1 through 6, respectively: (1) ischemic stroke with concomitant AF: 4.5%, 3.7%, 3.2%, 4.3%, 5.6%, and 8.4%; without concomitant AF: 1.5%, 1.5%, 2.0%, 3.0%, 3.7%, and 7% and (2) all-cause death with concomitant AF: 19.8%, 19.5%, 26.1%, 35.1%, 37.7%, and 45.5%; without concomitant AF: 7.6%, 8.3%, 17.8%, 25.6%, 27.9%, and 35.0%. At high CHA2DS2-VASc scores (≥4), the absolute risk of thromboembolism was high regardless of presence of AF (for a score of 4, 9.7% vs 8.2% for patients without and with concomitant AF, respectively; overall P<.001 for interaction). C statistics and negative predictive values indicate that the CHA2DS2-VASc score performed modestly in this HF population with and without AF (for ischemic stroke, 1-year C statistics, 0.67 [95% CI, 0.65-0.68] and 0.64 [95% CI, 0.61-0.67], respectively; 1-year negative predictive values, 92% [95% CI, 91%-93%] and 91% [95% CI, 88%-95%], respectively). CONCLUSIONS AND RELEVANCE: Among patients with incident HF with or without AF, the CHA2DS2-VASc score was associated with risk of ischemic stroke, thromboembolism, and death. The absolute risk of thromboembolic complications was higher among patients without AF compared with patients with concomitant AF at high CHA2DS2-VASc scores. However, predictive accuracy was modest, and the clinical utility of the CHA2DS2-VASc score in patients with HF remains to be determined.

Broad versus narrow research questions in evidence synthesis: A parallel to (and plea for) estimands.

There has been a transition from broad to more specific research questions in the practice of network meta-analysis (NMA). Such convergence is also taking place in the context of individual registrational trials, following the recent introduction of the estimand framework, which is impacting the design, data collection strategy, analysis and interpretation of clinical trials. The language of estimands has much to offer to NMA, particularly given the "narrow" perspective of treatments and target populations taken in health technology assessment.

Offspring preterm birth and birth size are related to long-term risk of maternal diabetes.

The aim of the study is to investigate the association between gestational age, birth size, and the long-term risk of maternal diabetes. We conducted a nation-wide prospective follow-up study of the cohort of all Danish women with a singleton delivery in 1982/1983 (index delivery) and no history of diabetes (n = 100,669). Registries were used to extract information on patients with a hospital or outpatient diagnosis of diabetes, subsequent deliveries, and death/emigration in the period from the index delivery until the end of 2006. The association between the maternal risk of diabetes and the index gestational age and index offspring birth size (birth weight adjusted for gestational age) was investigated by using Cox proportional hazards regression models stratified according to young (≤33 years) and old age (>33 years). During a median follow-up period of 24 years, 2,021 women (2.0 %) were diagnosed as having diabetes. The risk of maternal diabetes was positively associated with increasing index birth size and negatively associated with increasing duration of index gestation in both age strata. Among young women, the highest hazard ratios were found for the exposure category of large index offspring birth size (adjusted HR 9.0, 95 % CI 6.17-13.12) and a preterm delivery at 32-37 weeks (adjusted HR 2.22, 95 % CI 1.46-3.40). Offspring preterm birth and large size for gestational age at birth are associated with increased risk of maternal diabetes.

Donor site morbidity associated with autogenous bone harvesting from the ascending mandibular ramus.

PURPOSE: The objective of the present retrospective study was to assess long-term morbidity and postoperative complications after autogenous bone harvesting from the ascending mandibular ramus. MATERIALS AND METHODS: Bone harvesting from the ascending mandibular ramus was conducted in a consecutive case series, including 325 patients, at The Department of Oral and Maxillofacial Surgery, Aalborg University Hospital, Denmark from January 1, 2000 to December 31, 2010. Records and radiographs were retrospectively analyzed. RESULTS: Temporary neurosensory disturbances in the inferior alveolar nerve were found in 6.1% of the patients. Only 0.5% of the patients had permanent neurosensory disturbances. Severe hematoma occurred in 20 patients, while infection occurred in only 1 patient. CONCLUSIONS: Within the limitations of a retrospective case series study, the present study suggests that harvesting of autogenous bone from the ascending mandibular ramus is a safe surgical procedure with minimal donor site morbidity and few postoperative complications.

An Indirect Comparison of Basal Insulin Plus Once-Weekly Semaglutide and Fully Optimised Basal-Bolus Insulin in Type 2 Diabetes.

INTRODUCTION: To date, there have been few head-to-head comparisons between semaglutide once-weekly (OW) and short-acting meal-time insulin in participants with type 2 diabetes (T2D) treated with basal insulin and requiring treatment intensification. This indirect comparison evaluated the effects of these regimens on glycated haemoglobin (HbA1c), body weight, hypoglycaemia, and other clinically relevant outcomes. METHODS: A post-hoc, unanchored, individual participant data meta-analysis was conducted on the basis of data from single treatment arms in the SUSTAIN 5 and DUAL 7 trials. Semaglutide 0.5 mg OW and 1.0 mg OW plus basal insulin were compared with an optimised (treat-to-target) basal-bolus regimen of insulin glargine and insulin aspart over 26 weeks, using regression adjustment to account for baseline differences between the trials. RESULTS: Over 26 weeks, semaglutide 1.0 mg OW plus basal insulin reduced mean HbA1c by significantly more than the basal-bolus regimen (treatment difference: - 0.36%; p = 0.003), while semaglutide 0.5 mg OW plus basal insulin was comparable with basal-bolus insulin (treatment difference: 0.08%, p = 0.53). Both doses of semaglutide were associated with significant weight loss relative to insulin intensification (treatment differences: 6.8-9.4 kg; p < 0.001). At both doses, semaglutide intensification required less basal insulin per day than bolus intensification, and more participants on semaglutide met HbA1c targets of < 7.0% and ≤ 6.5% without hypoglycaemia or weight gain (odds ratio [OR] for < 7.0%, 21.9; OR for ≤ 6.5%, 16.2; both p < 0.001). CONCLUSIONS: In T2D uncontrolled by basal insulin, intensification with semaglutide 1.0 mg OW was associated with better glycaemic control, weight loss, and reduced hypoglycaemia versus a basal-bolus regimen, while limiting the treatment burden associated with frequent injections. Clinicians could consider treatment intensification with semaglutide when T2D is uncontrolled by basal insulin, especially when weight management is a priority. Effective glycaemic control coupled with weight management can alleviate the burden of diabetes-associated complications.

Continuous Glucose Monitoring Sensor Glucose Levels and Insulin Pump Infusion Set Wear-Time During Treatment with Fast-Acting Insulin Aspart: A Post Hoc Analysis of Onset 5.

Background: In the onset 5 trial, fast-acting insulin aspart (faster aspart) was noninferior to insulin aspart (IAsp) for change from baseline glycated hemoglobin at 16 weeks, when used in continuous subcutaneous insulin infusion by participants with type 1 diabetes. The aim of this post hoc analysis was to investigate whether infusion set wear-time was associated with changes in sensor glucose, measured using continuous glucose monitoring (CGM). Materials and Methods: This was a post hoc analysis of onset 5 data. Mean infusion set wear-time and duration of CGM-wearing period were assessed. Mean CGM sensor glucose 24 h before and 24 h after were used to calculate the before-after difference (CGM sensor glucose drift). Results: Mean infusion set wear-time was 2.9 and 3.0 days in the faster aspart and IAsp arms, respectively. At 16 weeks, the average duration of the CGM wearing period was 13.7 and 13.8 days, respectively. Mean CGM sensor glucose before versus after an infusion set change, at week 16, was 10.14 versus 9.39 mmol/L with faster aspart and 9.48 versus 9.47 mmol/L with IAsp. The estimated treatment difference in CGM sensor glucose drift at 16 weeks for faster aspart versus IAsp was +0.72 mmol/L (95% confidence interval: 0.48-0.96, P < 0.001). Conclusions: Mean infusion set wear-time and duration of CGM-wearing period were similar for faster aspart and IAsp. A significantly greater upward drift in CGM sensor glucose values measured during an infusion set wearing period was observed with faster aspart versus IAsp. Clinical trial registration: NCT02825251.

Exploring dietary patterns by using the treelet transform.

Principal component analysis (PCA) has been used extensively in the field of nutritional epidemiology to derive patterns that summarize food and nutrient intake, but interpreting it can be difficult. The authors propose the use of a new statistical technique, the treelet transform (TT), as an alternative to PCA. TT combines the quantitative pattern extraction capabilities of PCA with the interpretational advantages of cluster analysis and produces patterns involving only naturally grouped subsets of the original variables. The authors compared patterns derived using TT with those derived using PCA in a study of dietary patterns and risk of myocardial infarction among 26,155 male participants in a prospective Danish cohort. Over a median of 11.9 years of follow-up, 1,523 incident cases of myocardial infarction were ascertained. The 7 patterns derived with TT described almost as much variation as the first 7 patterns derived with PCA, for which interpretation was less clear. When the authors used multivariate Cox regression models to estimate relative risk of myocardial infarction, the significant risk factors were comparable whether the model was based on PCA or TT factors. The present study shows that TT may be a useful alternative to PCA in epidemiologic studies, leading to patterns that possess comparable explanatory power and are simple to interpret.

Efficacy and Safety of Fast-Acting Insulin Aspart in People with Type 1 Diabetes Using Carbohydrate Counting: A Post Hoc Analysis of Two Randomised Controlled Trials.

INTRODUCTION: Insulin dosing based on carbohydrate counting is the gold standard for improving glycaemic control in type 1 diabetes (T1D). This post hoc analysis aimed to explore the efficacy and safety of fast-acting insulin aspart (faster aspart) according to bolus dose adjustment method in people with T1D. METHODS: Post hoc analysis of two 26-week, treat-to-target, randomised trials investigating treatment with double-blind mealtime faster aspart, insulin aspart (IAsp), or open-label post-meal faster aspart (onset 1, n = 1143; onset 8, n = 1025). Participants with previous experience continued carbohydrate counting (onset 1, n = 669 [58.5%]; onset 8, n = 428 [41.8%]), while remaining participants used a bolus algorithm. RESULTS: In onset 1, HbA1c reduction was statistically significantly in favour of mealtime faster aspart versus IAsp with carbohydrate counting (estimated treatment difference [ETD 95% CI] - 0.19% [- 0.30; - 0.09]; - 2.08 mmol/mol [- 3.23; - 0.93]). In onset 8, there was no statistically significant difference in HbA1c reduction with either dose adjustment method, although a trend towards improved HbA1c was observed for mealtime faster aspart with carbohydrate counting (ETD - 0.14% [- 0.28; 0.003]; - 1.53 mmol/mol [- 3.10; 0.04]). In both trials, bolus insulin doses and overall rates of severe or blood glucose-confirmed hypoglycaemia were similar between treatments across dose adjustment methods. CONCLUSION: For people with T1D using carbohydrate counting, mealtime faster aspart may offer improved glycaemic control versus IAsp, with similar insulin dose and weight gain and no increased risk of hypoglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01831765 (onset 1) and NCT02500706 (onset 8). FUNDING: Novo Nordisk.

A population-based observational study of dental caries among survivors of childhood cancer.

BACKGROUND: The few published studies on caries among childhood cancer survivors are small and their results are conflicting. The study aim was to examine the risk of dental caries among children who have survived cancer. PROCEDURE: We included 299,426 7-year-old, 313,461 12-year-old, and 301,930 15-year-old children born between 1984 and 1988 in a nationwide population-based study linking records from Danish Cancer Registry with records from the national database on oral health. Children whose dental examinations had been preceded by a cancer diagnosis (288 7-year-old, 459 12-year-old, and 526 15-year-old) were compared with children without cancer according to presence of caries: caries-free children; children with any caries experience; and children with severe caries experience (i.e., caries in one or more smooth tooth surface). RESULTS: Children diagnosed with cancer before the age of 5 years did not have increased caries prevalence in permanent teeth at ages 12; and 15. Children diagnosed with cancer between 5 and 6 years of age had an increased prevalence of severe caries at age 12 years (prevalence ratio (PR) = 1.59 (95% CI: 1.09-2.31; P = 0.02)), but this difference disappeared by age 15. For children diagnosed with cancer at 5 or 6 years of age and who received radiation therapy the PR of severe caries was 1.52 (95% CI: 0.97-2.37; P = 0.07), 2.13 (95% CI: 0.89-5.10; P = 0.09), and 0.31 (95% CI: 0.07-1.45; P = 0.13) at ages seven, 12 and 15 years respectively. CONCLUSION: Cancer and cancer treatment during childhood are risk factors for caries.

Trans fatty acids in adipose tissue and risk of myocardial infarction: A case-cohort study.

BACKGROUND: The risk of coronary heart disease associated with intake of individual trans fatty acids (TFAs) is not clear. Adipose tissue content of TFAs is a biomarker of TFA intake and metabolism. OBJECTIVE: We investigated the rate of myocardial infarction (MI) associated with the adipose tissue content of total 18:1t, isomers of 18:1t (18:1 Δ6-10t and 18:1 Δ11t) and 18:2 Δ9c, 11t. METHODS: A case-cohort study, nested within the Danish Diet, Cancer and Health cohort (n = 57,053), was conducted, which included a random sample (n = 3156) of the total cohort and all incident MI cases (n = 2148) during follow-up (14 years). Information on MI cases was obtained by linkage with nationwide registers and validated. Adipose tissue was taken from the participants buttocks and the fatty acid composition was determined by gas chromatography. RESULTS: Women with higher adipose tissue content of total 18:1t had a 57% higher MI rate (quintiles 5 versus 1, hazard ratio, 1.57; 95% confidence interval, 1.12-2.20; P-trend = 0.011) and women with higher content of 18:1 Δ6-10t had a 76% higher MI rate (quintiles 5 versus 1, hazard ratio, 1.76; 95% confidence interval, 1.23-2.51; P-trend = 0.002). No association between 18:1 Δ11t content and MI rate was observed. In men, no associations between adipose tissue content of total 18:1t and 18:1 Δ6-10t and MI rate were observed. However, men with higher content of 18:1 Δ11t had a 48% higher MI rate (quintiles 5 versus 1, hazard ratio, 1.48; 95% confidence interval, 1.17-1.86; P-trend = 0.003). Adipose tissue content of 18:2 Δ9c, 11t was not associated with MI rate in women or men. CONCLUSIONS: Adipose tissue content of 18:2 Δ9c, 11t was not associated with MI rate in women or men, whereas higher contents of isomers of 18:1t were associated with higher MI rates but the associations for individual 18:1t isomers differed, however, in women and men.

Anticoagulant therapy after venous thromboembolism and 10-year mortality.

BACKGROUND: Pulmonary embolism (PE) is associated with a higher long-term mortality than deep vein thrombosis (DVT). This association may be related to inadequate antithrombotic therapy. METHODS: Incident VTE patients during the period 1997-2012 were identified in Danish nationwide registries. Two landmark populations were defined, consisting of patients alive at 30 days (30 d), and at 180 days (180 d) after discharge. Patients were classified according to anticoagulant usage at the landmark (30 d: prescription purchase 0-30 d post-discharge; 180 d: prescription purchase in 0-30 d and 90-180 d). Mortality rates were compared using multivariate Cox regression. RESULTS: The 30 d mortality risk among PE patients was high compared to DVT patients (19.9% vs. 4.4%). In the 30 d-landmark population (n=62695), 34.9% of DVT patients and 21.3% of PE patients had not redeemed a prescription for anticoagulants. There was no material difference in 10-year mortality between anticoagulated PE patients and anticoagulated DVT patients. There was a higher 10-year mortality rate among non-anticoagulated PE patients compared to anticoagulated DVT patients (MRR: 1.26, 95% CI: 1.20-1.33). Findings in the 180 d-landmark population also indicated materially similar 10-year mortality rates between anticoagulated PE patients and anticoagulated DVT patients. CONCLUSIONS: The 10-year mortality rate of patients surviving the initial 30 d critical period following incident PE was not increased compared to patients with incident DVT, as long as patients initiated and persisted with anticoagulant therapy. Increased focus on antithrombotic therapy in PE patients and reasons for early therapy discontinuation may be warranted.