Identifying safe diagnostic algorithms for sentinel lymph node mapping in high-risk endometrial cancer: The SENTIREC-endo study.

INTRODUCTION: It is unclear if sentinel node (SLN) mapping can replace pelvic- (PLD) and paraaortic lymphadenectomy (PALD) for high-risk endometrial cancer (EC). A diagnostically safe surgical algorithm, taking failed mapping cases into account, is not defined. We aimed to investigate the diagnostic accuracy of SLN mapping algorithms in women with exclusively high-risk EC. METHODS: We undertook a prospective national diagnostic cohort study of SLN mapping in women with high-risk EC from March 2017 to January 2023. The power calculation was based on the negative predictive value (NPV). Women underwent SLN mapping, PLD and PALD besides removal of suspicious and any FDG/PET-positive lymph nodes. Accuracy analyses were performed for five algorithms. RESULTS: 170/216 included women underwent SLN mapping, PLD and PALD and were included in accuracy analyses. 42/170 (24.7%) had nodal metastasis. The algorithm SLN and PLD in case of failed mapping, demonstrated a sensitivity of 86% (95% CI 74-100) and an NPV of 96% (95% CI 91-100). The sensitivity increased to 93% (95% CI 83-100) and the NPV to 98% (95% CI 94-100) if PLD was combined with removal of any PET-positive lymph nodes. Equivalent results were obtained if PLD and PALD were performed in non-mapping cases; sensitivity 93% (95% CI 83-100) and NPV 98% (95% CI 95-100). CONCLUSION: SLN-mapping is a safe staging procedure in women with high-risk EC if strictly adhering to a surgical algorithm including removal of any PET-positive lymph nodes independent of location and PLD or PLD and PALD in case of failed mapping.

Prognostic Value of Coronary CT Angiography-derived Fractional Flow Reserve on 3-year Outcomes in Patients with Stable Angina.

Background The prognostic value of coronary CT angiography (CTA)-derived fractional flow reserve (FFR) beyond 1-year outcomes and in patients with high levels of coronary artery calcium (CAC) is uncertain. Purpose To assess the prognostic value of coronary CTA-derived FFR test results on 3-year clinical outcomes in patients with coronary stenosis and among a subgroup of patients with high levels of CAC. Materials and Methods This study represents a 3-year follow-up of patients with new-onset stable angina pectoris who were consecutively enrolled in the Assessing Diagnostic Value of Noninvasive CT-FFR in Coronary Care, known as ADVANCE (ClinicalTrials.gov: NCT02499679) registry, between December 2015 and October 2017 at three Danish sites. A high CAC was defined as an Agatston score of at least 400. A lesion-specific coronary CTA-derived FFR value of 2 cm with distal-to-stenosis value at or below 0.80 represented an abnormal test result. The primary end point was a composite of all-cause death and nonfatal spontaneous myocardial infarction. Event rates were estimated using the one-sample binomial model, and relative risk was compared between participants stratified by results of coronary CTA-derived FFR. Results This study included 900 participants: 523 participants with normal results (mean age, 64 years ± 9.6 [SD]; 318 male participants) and 377 with abnormal results from coronary CTA-derived FFR (mean age, 65 years ± 9.6; 264 male participants). The primary end point occurred in 11 of 523 (2.1%) and 25 of 377 (6.6%) participants with normal and abnormal coronary CTA-derived FFR results, respectively (relative risk, 3.1; 95% CI: 1.6, 6.3; P < .001). In participants with high CAC, the primary end point occurred in four of 182 (2.2%) and 19 of 212 (9.0%) participants with normal and abnormal coronary CTA-derived FFR results, respectively (relative risk, 4.1; 95% CI: 1.4, 11.8; P = .001). Conclusion In individuals with stable angina, a normal coronary CTA-derived FFR test result identified participants with a low 3-year risk of all-cause death or nonfatal spontaneous myocardial infarction, both in the overall cohort and in participants with high CAC scores. Clinical trial registration no. NCT02499679 Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Sinitsyn in this issue.

The SENTIREC-endo study - Risks and benefits of a national adoption of sentinel node mapping in low and intermediate risk endometrial cancer.

OBJECTIVE: The SENTIREC-endo study aims to investigate risks and benefits of a national protocolled adoption of sentinel lymph node (SLN) mapping in women with early-stage low-grade endometrial cancer (EC) with low- (LR) and intermediate-risk (IR) of lymph node metastases. METHODS: We performed a national multicenter prospective study of SLN-mapping in women with LR and IR EC from March 2017-February 2022. Postoperative complications were classified according to Clavien-Dindo. Lymphedema was assessed as a change score and as incidence of swelling and heaviness evaluated by validated patient-reported outcome measures at baseline and three months postoperatively. RESULTS: 627 women were included in the analyses; 458 with LR- and 169 with IR EC. The SLN detection rate was 94.3% (591/627). The overall incidence of lymph node metastases was 9.3% (58/627); 4.4% (20/458) in the LR- and 22.5% (38/169) in the IR group. Ultrastaging identified 62% (36/58) of metastases. The incidence of postoperative complications was 8% (50/627) but only 0.3% (2/627) experienced an intraoperative complication associated with the SLN procedure. The lymphedema change score was below the threshold for clinical importance 4.5/100 CI: (2.9-6.0), and the incidence of swelling and heaviness was low; 5.2% and 5.8%, respectively. CONCLUSION: SLN mapping in women with LR and IR EC carries a very low risk of early lymphedema and peri- and postoperative complications. The national change in clinical practice contributed to a more correct treatment allocation for both risk groups and thus supports further international implementation of the SLN technique in early stage, low grade EC.

Win-loss parameters for right-censored event data, with application to recurrent events.

The win ratio has become a popular method for comparing multiple event data between two groups in clinical cohort studies. The win ratio compares the event data in prioritized order, where the first prioritized event is death and a typical example for the second prioritized event is hospitalization. Literature is sparse on inference for win and loss parameters, including the win ratio, for censored event data. Inference for two prioritized censored event times has been developed for independent right-censoring. Many clinical studies include recurrent event data such as hospitalizations. In this article, we suggest inference for win-loss parameters for death and a recurrent event outcome under independent right-censoring. The small sample properties of the proposed method are studied in a simulation study showing that the variance formula is accurate even for small samples. The method is applied on a data set from a randomized clinical trial.

Comparing performance between clinics of an embryo evaluation algorithm based on time-lapse images and machine learning.

PURPOSE: This article aims to assess how differences in maternal age distributions between IVF clinics affect the performance of an artificial intelligence model for embryo viability prediction and proposes a method to account for such differences. METHODS: Using retrospectively collected data from 4805 fresh and frozen single blastocyst transfers of embryos incubated for 5 to 6 days, the discriminative performance was assessed based on fetal heartbeat outcomes. The data was collected from 4 clinics, and the discrimination was measured in terms of the area under ROC curves (AUC) for each clinic. To account for the different age distributions between clinics, a method for age-standardizing the AUCs was developed in which the clinic-specific AUCs were standardized using weights for each embryo according to the relative frequency of the maternal age in the relevant clinic compared to the age distribution in a common reference population. RESULTS: There was substantial variation in the clinic-specific AUCs with estimates ranging from 0.58 to 0.69 before standardization. The age-standardization of the AUCs reduced the between-clinic variance by 16%. Most notably, three of the clinics had quite similar AUCs after standardization, while the last clinic had a markedly lower AUC both with and without standardization. CONCLUSION: The method of using age-standardization of the AUCs that is proposed in this article mitigates some of the variability between clinics. This enables a comparison of clinic-specific AUCs where the difference in age distributions is accounted for.

Regression models for censored time-to-event data using infinitesimal jack-knife pseudo-observations, with applications to left-truncation.

Jack-knife pseudo-observations have in recent decades gained popularity in regression analysis for various aspects of time-to-event data. A limitation of the jack-knife pseudo-observations is that their computation is time consuming, as the base estimate needs to be recalculated when leaving out each observation. We show that jack-knife pseudo-observations can be closely approximated using the idea of the infinitesimal jack-knife residuals. The infinitesimal jack-knife pseudo-observations are much faster to compute than jack-knife pseudo-observations. A key assumption of the unbiasedness of the jack-knife pseudo-observation approach is on the influence function of the base estimate. We reiterate why the condition on the influence function is needed for unbiased inference and show that the condition is not satisfied for the Kaplan-Meier base estimate in a left-truncated cohort. We present a modification of the infinitesimal jack-knife pseudo-observations that provide unbiased estimates in a left-truncated cohort. The computational speed and medium and large sample properties of the jack-knife pseudo-observations and infinitesimal jack-knife pseudo-observation are compared and we present an application of the modified infinitesimal jack-knife pseudo-observations in a left-truncated cohort of Danish patients with diabetes.

SENTIREC - The sentinel node mapping in women with cervical cancer study - Patient-reported early lymphedema and its impact on quality of life.

OBJECTIVE: To evaluate patient-reported incidence and severity of early lymphedema and its impact on quality of life (QoL) after sentinel lymph node (SLN) mapping only and after SLN and pelvic lymphadenectomy (PL) in women undergoing surgery for early-stage cervical cancer. METHODS: In a national prospective multicenter study, we included women with early-stage cervical cancer from March 2017-January 2021 to undergo radical surgery including SLN mapping. Women with tumors >20 mm underwent completion PL. The incidence and severity of early lymphedema and its influence on QoL were evaluated using validated patient-reported outcome measures before surgery and three months postoperative. We investigated changes over time using linear regression. RESULTS: Two hundred of 245 (81.6%) included women completed questionnaires at baseline and three months postoperatively. The incidence of early lymphedema was 5.6% (95% CI 2.1-11.8%) and 32.3% (95% CI 22.9-42.7%) in women who underwent SLN mapping only and SLN + PL, respectively. Lymphedema symptoms in the legs, genitals, and groins increased in both groups postoperatively but three times more in women who underwent PL. Lymphedema symptoms after SLN + PL significantly impaired physical performance (p = 0.001) and appearance (p = 0.007). Reporting lymphedema was significantly associated with impaired body image, physical-, role-, and social functioning, and a high level of fatigue. CONCLUSIONS: SLN mapping alone carries a low risk of lymphedema in women undergoing surgery for early-stage cervical cancer. In contrast, completion PL is associated with a high incidence of early lymphedema. Reporting lymphedema is associated with significant impairment of several physical, psychological, and social aspects of QoL.

Replacing Red Meat with Other Nonmeat Food Sources of Protein is Associated with a Reduced Risk of Type 2 Diabetes in a Danish Cohort of Middle-Aged Adults.

BACKGROUND: Few cohort studies have modelled replacements of red meat with other sources of protein on subsequent risk of type 2 diabetes using dietary changes. OBJECTIVES: To determine whether replacing red meat with other food sources of protein is associated with a lower risk of type 2 diabetes. METHODS: We used data from the Danish Diet, Cancer, and Health cohort (n = 39,437) of middle-aged (55-72 years old) men and women who underwent 2 dietary assessments roughly 5 years apart to investigate dietary changes. The pseudo-observation method was used to model the average exposure effect of decreasing the intake of red meat while increasing the intake of either poultry, fish, eggs, milk, yogurt, cheese, whole grains, or refined grains on the subsequent 10-year risk of developing type 2 diabetes, compared with no changes in the intakes of these foods. RESULTS: Replacing 1 serving/day (100 g/day) of red meat with 1 serving/day of eggs [risk difference (RD), -2.7%; 95% CI: -4.0 to -1.1%; serving size: 50 g/day], milk (RD, -1.2%; 95% CI: -2.1 to -0.4%; 200 g/day), yogurt (RD, -1.5%; 95% CI: -2.4 to -0.7%; 70 g/day), whole grains (RD, -1.7%; 95% CI: -2.5 to -0.9%; 30 g/day), or refined grains (RD, -1.2%; 95% CI: -2.0 to -0.3%; 30 g/day) was associated with a reduced risk of type 2 diabetes. Analyses of replacements with poultry or cheese, but not fish, also suggested a lower risk, but with wide CIs. After further adjustment for potential mediators (BMI, waist circumference, and history of hypertension or hypercholesterolemia), only the replacement with eggs was associated with a reduced risk (RD, -1.7%; 95% CI: -3.0 to -0.5%; 50 g/day). CONCLUSIONS: Replacing red meat with eggs in middle-aged adults may reduce the risk of type 2 diabetes. In models not adjusted for potential mediators, replacing red meat with milk, yogurt, whole grains, or refined grains was also associated with a reduced risk of type 2 diabetes.

From FIGO-2009 to FIGO-2018 in women with early-stage cervical cancer; Does the revised staging reflect risk groups?

OBJECTIVES: We aimed to evaluate if the revised staging according to FIGO-2018 in early-stage cervical cancer correctly predicts the risk for nodal metastases. METHODS: We reallocated 245 women with early-stage cervical cancer from FIGO-2009 to FIGO-2018 stages using data from a national, prospective cohort study on sentinel lymph node (SLN) mapping. We used univariate and multivariate binary regression models to investigate the association between FIGO-2018 stages, tumor characteristics, and nodal metastases. RESULTS: Stage migration occurred in 54.7% (134/245) (95% CI 48.2-61.0), due to tumor size or depth of invasion (71.6%, 96/134) and nodal metastases (28.4%, 38/134). Imaging preoperatively upstaged 7.3% (18/245); seven had nodal metastatic disease on final pathology. Upstaging occurred in 49.8% (122/245) (95% CI 43.4-56.2%) and downstaging to FIGO-2018 IA stages in 4.9% (12/245) (95% CI 2.6-8.4). The tumor size ranged from 3.0-19.0 mm in women with FIGO-2018 IA tumor characteristics, and none of the 14 women had nodal metastases. In multivariate analysis, risk factors significantly associated with nodal metastases were FIGO-2018 ≥ IB2 (RR 5.01, 95% CI 2.30-10.93, p < 0.001), proportionate depth of invasion >2/3 (RR 1.88, 95% CI 1.05-3.35, p = 0.033), and lymphovascular space invasion (RR 5.56, 95% CI 2.92-10.62, p < 0.001). CONCLUSIONS: The FIGO-2018 revised staging system causes stage migration for a large proportion of women with early-stage cervical cancer. Women who were downstaged to FIGO-2018 IA stages did not have nodal metastatic disease. The attention on depth of invasion rather than horizontal dimension seems to correctly reflect the risk of nodal metastases.

Sentinel lymph node mapping in early-stage cervical cancer - A national prospective multicenter study (SENTIREC trial).

OBJECTIVES: Sentinel lymph node (SLN) mapping may replace staging radical pelvic lymphadenectomy in women with early-stage cervical cancer. In a national multicenter setting, we evaluated SLN mapping in women with early-stage cervical cancer and investigated the accuracy of SLN mapping and FDG-PET/CT in tumors >20 mm. METHODS: We prospectively included women with early-stage cervical cancer from March 2017-January 2021 to undergo SLN mapping. Women with tumors >20 mm underwent completion pelvic lymphadenectomy and removal of FDG-PET/CT positive nodes. We determined SLN detection rates, incidence of nodal disease, sensitivity and negative predictive value (NPV) of SLN mapping, and the sensitivity, specificity, NPV, and positive predictive value (PPV) of FDG-PET/CT. RESULTS: We included 245 women, and 38 (15.5%) had nodal metastasis. The SLN detection rate was 96.3% (236/245), with 82.0% (201/245) bilateral detection. In a stratified analysis of 103 women with tumors >20 mm, 27 (26.2%) had nodal metastases. The sensitivity of SLN mapping adhering to the algorithm was 96.3% (95% CI 81.0-99.9%) and the NPV 98.7% (95% CI 93.0-100%). For FDG-PET/CT imaging the sensitivity was 14.8% (95% CI 4.2-33.7%), the specificity 85.5% (95% CI 75.6-92.5%), the NPV 73.9% (95% CI 63.4-82.7%), and the PPV 26.7% (95% CI 7.8-55.1%). CONCLUSIONS: SLN mapping seems to be an adequate staging procedure in early-stage cervical cancer tumors ≤20 mm. In tumors >20 mm, SLN mapping is highly sensitive but demands full adherence to the SLN algorithm. We recommend completion pelvic lymphadenectomy in tumors >20 mm until the oncological safety is established. FDG-PET/CT for nodal staging of women with early-stage cervical cancer seems limited.

Neonatal jaundice and autism spectrum disorder: a systematic review and meta-analysis.

BACKGROUND: Two meta-analyses concluded that jaundice was associated with an increased risk of autism. We hypothesize that these findings were due to methodological limitations of the studies included. Neonatal jaundice affects many infants and risks of later morbidity may prompt physicians towards more aggressive treatment. METHODS: To conduct a systematic literature review and a meta-analysis of the association between neonatal jaundice and autism with particular attention given to low risk of bias studies. Pubmed, Scopus, Embase, Cochrane, and Google Scholar were searched for publications until February 2019. Data was extracted by use of pre-piloted structured sheets. Low risk of bias studies were identified through predefined criteria. RESULTS: A total of 32 studies met the inclusion criteria. The meta-analysis of six low risk of bias studies showed no association between neonatal jaundice and autism; cohort studies risk ratio 1.09, 95% CI, 0.99-1.20, case-control studies odds ratio 1.29 95% CI 0.95, 1.76. Funnel plot of all studies suggested a high risk of publication bias. CONCLUSIONS: We found a high risk of publication bias, selection bias, and potential confounding in all studies. Based on the low risk of bias studies there was no convincing evidence to support an association between neonatal jaundice and autism. IMPACT: Meta-analysis of data from six low risk of bias studies indicated no association between neonatal jaundice and autism spectrum disorder. Previous studies show inconsistent results, which may be explained by unadjusted confounding and selection bias. Funnel plot suggested high risk of publication bias when including all studies. There is no evidence to suggest jaundice should be treated more aggressively to prevent autism.

Regression models for interval censored data using parametric pseudo-observations.

BACKGROUND: Time-to-event data that is subject to interval censoring is common in the practice of medical research and versatile statistical methods for estimating associations in such settings have been limited. For right censored data, non-parametric pseudo-observations have been proposed as a basis for regression modeling with the possibility to use different association measures. In this article, we propose a method for calculating pseudo-observations for interval censored data. METHODS: We develop an extension of a recently developed set of parametric pseudo-observations based on a spline-based flexible parametric estimator. The inherent competing risk issue with an interval censored event of interest necessitates the use of an illness-death model, and we formulate our method within this framework. To evaluate the empirical properties of the proposed method, we perform a simulation study and calculate pseudo-observations based on our method as well as alternative approaches. We also present an analysis of a real dataset on patients with implantable cardioverter-defibrillators who are monitored for the occurrence of a particular type of device failures by routine follow-up examinations. In this dataset, we have information on exact event times as well as the interval censored data, so we can compare analyses of pseudo-observations based on the interval censored data to those obtained using the non-parametric pseudo-observations for right censored data. RESULTS: Our simulations show that the proposed method for calculating pseudo-observations provides unbiased estimates of the cumulative incidence function as well as associations with exposure variables with appropriate coverage probabilities. The analysis of the real dataset also suggests that our method provides estimates which are in agreement with estimates obtained from the right censored data. CONCLUSIONS: The proposed method for calculating pseudo-observations based on the flexible parametric approach provides a versatile solution to the specific challenges that arise with interval censored data. This solution allows regression modeling using a range of different association measures.

Changes in intake of dairy product subgroups and risk of type 2 diabetes: modelling specified food substitutions in the Danish Diet, Cancer and Health cohort.

PURPOSE: We investigated the association between an increased intake of one dairy product subgroup at the expense of another within a 5-year period and the subsequent 10-year risk of type 2 diabetes. METHODS: The cohort included 39,393 adults with two measurements of diet assessed using food frequency questionnaires (FFQ) administered in 1993-1997 and 1999-2003. Dairy products were milk (skimmed, semi-skimmed, whole fat), buttermilk, low-fat yogurt, whole-fat yogurt, cheese and butter. Type 2 diabetes cases were ascertained from the Danish National Diabetes Register. The pseudo-observation method was used to calculate risk differences (RD) with 95% confidence intervals (CI). The data were analysed in age strata to fulfil the assumption of independent entry. RESULTS: Among participants aged 56-59 years at completion of the follow-up FFQ, increased intake of whole-fat yogurt in place of skimmed, semi-skimmed or whole-fat milk was associated with a reduced risk (RD% [95% CI]: - 0.8% [- 1.3, - 0.2]; - 0.6% [- 1,1, - 0.1]; - 0.7 [- 1.2, - 0.1]; per 50 g/d, respectively). Among participants aged 60-64 and 65-72, substitution of skimmed milk for semi-skimmed milk was associated with an increased risk of type 2 diabetes (0.5% [0.2, 0.7]; 0.4% [0.1, 0.7]; per 50 g/d, respectively). Similar patterns of associations were found after adjustment for potential mediators. CONCLUSION: Our results suggest that substitution of whole-fat yogurt for milk among those aged 56-59 decreases risk of type 2 diabetes and substitution of skimmed milk for semi-skimmed milk may increase the risk among those aged 60-64 and 65-72.

Computed Tomography-Derived Fractional Flow Reserve in Patients With Chronic Coronary Syndrome: A Real-World Cohort Study.

OBJECTIVE: This study aimed to investigate the outcome of computed tomography (CT) angiography with optional CT-derived fractional flow reserve (FFRCT) of intermediate-range coronary artery disease in non-emergent patients referred on a suspicion of chronic coronary syndrome. METHODS: Patients were classified as high risk and low-intermediate risk according to the presence of typical angina or either atypical or nonangina chest pain. Outcome was assessed as the cumulative incidence proportion of a composite end point of unstable angina pectoris, unplanned revascularization, nonfatal myocardial infarction, and all-cause mortality. RESULTS: The study included 743 patients. Mean follow-up was 2.2 (range, 0.1-2.5) years. Low-intermediate-risk and high-risk patients who had invasive coronary angiography deferred had comparable proportions of adverse events (1.4% vs 2.6% [P = 0.27]). Adverse events in high-risk patients with FFRCT >0.80 was 3.3% versus 1.4% in patients where no additional testing was performed (P = 0.79). CONCLUSIONS: Computed tomography-derived fractional flow reserve >0.8 conveys an excellent prognosis. Computed tomography angiography with optional FFRCT allows for the safe cancellation of invasive coronary angiography in high-risk patients.

Repeat pulmonary vein isolation in patients with atrial fibrillation: low ablation index is associated with increased risk of recurrent arrhythmia.

OBJECTIVES: We aimed to investigate the predictors of recurrent arrhythmia after repeated pulmonary vein isolation (PVI) performed in the era of contact force without additional substrate ablation. One of the predictors studied, ablation index (AI), incorporates power, contact force, and time in a weighted formula and is reported to predict lesion size in animals. Design. Consecutive patients (n = 108) undergoing repeat PVI without additional substrate modification using a contact force sensing catheter were included retrospectively at a tertiary center. All ablation points were analyzed offline. A new variable, normalized AI (AI corrected for the location of the lesion-anterior vs. posterior) was calculated. The patients were systematically followed with clinical visit and 12-lead ECG as well as review of the regional electronic patient files at 3 and 12 months after the procedure with 5-day Holter at 12 months. Results. Electrical reconnection to at least one pulmonary vein (PV) was seen in 97% of the patients. The recurrence rate was 35%. There was no recurrence in patients with nAI above 1.15 (n = 26). Patients with electrical reconnection of up to two PVs had a higher risk of recurrence compared with patients having electrical reconnection of three or four PVs (p = .003), and this risk was especially high in patients with persistent atrial fibrillation (69 [39-91]%). Conclusions. The risk of recurrence is higher in patients with ablations performed with low levels of AI and in patients with reconnection to up to two PVs. Our data may indicate the need for higher target levels of AI during repeat PVI than normally used during de-novo PVI.

Depression and Uptake of Oral Anticoagulation Therapy in Patients With Atrial Fibrillation: A Danish Nationwide Cohort Study.

BACKGROUND: Oral anticoagulation therapy (OAT) in patients with atrial fibrillation (AF) is a highly important preventive intervention, perhaps especially in those with comorbid depression, who have a worse prognosis. However, OAT may pose particular challenges in depressed patients. OBJECTIVES: To assess whether AF patients with depression have lower OAT uptake. METHODS: This nationwide register-based 2005-2016 cohort study of all Danes with AF and OAT indication (CHA2DS2VASc stroke risk score ≥2) assessed OAT initiation within 90 days in those with incident AF (N=147,162) and OAT prevalence in those with prevalent AF (N=192,656). The associations of depression with both outcomes were estimated in regression analyses with successive adjustment for socioeconomic characteristics and somatic and psychiatric comorbidity. RESULTS: Comorbid depression was significantly associated with lower frequency of OAT initiation in incident AF patients {adjusted proportion differences (aPDs): -6.6% [95% confidence interval (CI), -7.4 to -5.9]} and lower prevalence of OAT [aPD: -4.2% (95% CI, -4.7 to -3.8)] in prevalent AF patients. Yet, the OAT uptake increased substantially during the period, particularly in depressed patients [aPD for OAT prevalence in 2016: -0.8% (95% CI, -1.6 to -0.0)]. CONCLUSIONS: Comorbid depression was associated with a significantly lower OAT uptake in patients with AF, which questions whether depressed patients receive sufficient support to manage this consequential cardiac condition. However, a substantial increase in the overall OAT uptake and a decrease of the depression-associated deficit in OAT were seen over the period during which OAT was developed through the introduction of new oral anticoagulation therapy.

Regression models using parametric pseudo-observations.

Pseudo-observations based on the nonparametric Kaplan-Meier estimator of the survival function have been proposed as an alternative to the widely used Cox model for analyzing censored time-to-event data. Using a spline-based estimator of the survival has some potential benefits over the nonparametric approach in terms of less variability. We propose to define pseudo-observations based on a flexible parametric estimator and use these for analysis in regression models to estimate parameters related to the cumulative risk. We report the results of a simulation study that compares the empirical standard errors of estimates based on parametric and nonparametric pseudo-observations in various settings. Our simulations show that in some situations there is a substantial gain in terms of reduced variability using the proposed parametric pseudo-observations compared with the nonparametric pseudo-observations. The gain can be measured as a reduction of the empirical standard error by up to about one third; corresponding to an additional 125% larger sample size. We illustrate the use of the proposed method in a brief data example.

Risk of selection bias due to non-participation in a cohort study on pubertal timing.

BACKGROUND: Non-participation in aetiologic studies of pubertal timing is frequent. However, little effort has been given to explore the risk and potential impact of selection bias in studies of pubertal timing. OBJECTIVE: We aimed to explore the risk of selection bias due to non-participation in a newly established puberty cohort. METHODS: We evaluated whether three maternal exposures chosen a priori (pre-pregnancy obesity, smoking, and alcohol drinking during pregnancy) were associated with participation, whether pubertal timing was associated with participation, and whether selection bias influenced the associations between these exposures and pubertal timing. In total, 22 439 children from the Danish National Birth Cohort born 2000-2003 were invited to the Puberty Cohort and 15 819 (70%) participated. Exposures were self-reported during pregnancy. Pubertal timing was measured using a previously validated marker, "the height difference in standard deviations" (HD:SDS), which is the difference between pubertal height and adult height, both in standard deviations. For this study, pubertal height at around 13 years in sons and around 11 years in daughters was obtained from an external database, and adult height was predicted based on parental height reported by mothers. RESULTS: Participation was associated with most exposures but not with pubertal timing, measured by HD:SDS. The associations between exposures and HD:SDS were comparable for participants only and all invited for participation. CONCLUSION: In conclusion, the risk of selection bias in aetiologic studies on pubertal timing in the Puberty Cohort appears minimal.

Outcome of hybrid compared to conventional revascularization in multivessel coronary artery disease.

OBJECTIVES: Evaluation of 3-year clinical outcome of hybrid myocardial revascularization (HMR) compared to conventional revascularization strategies in patients with multivessel coronary artery disease involving the proximal left anterior descending artery. Design. Retrospective matched cohort study based on a prospective feasibility study including 103 elective patients undergoing staged HMR from October 2010 until February 2012. The Western Denmark Heart Registry was used to identify patients who underwent coronary artery bypass grafting (CABG) and multivessel percutaneous coronary intervention (PCI) by matching on number of diseased vessels, age and comorbidity score. Primary endpoint was the composite rate of major adverse cardiovascular and cerebrovascular events (MACCE) at 3-year follow-up. Secondary endpoints included individual MACCE components, acute kidney injury, and cardiovascular readmissions. Results. There was no difference between MACCE in the three groups (HMR 31.1%; CABG 20.4%; PCI 20.4%, p = .11). Estimates of repeat revascularization were significantly increased with HMR versus CABG. In the CABG group, fewest patients required cardiovascular readmissions though with the highest incidence of acute kidney injury. Conclusions. HMR was not superior with respect to MACCE compared with CABG and PCI. It may, however, represent a safe alternative to conventional revascularization treatment considering the specific procedure-associated morbidity.

Methods matter: exploring the 'too much, too soon' theory, part 1: causal questions in sports injury research.

BACKGROUND: It is widely accepted that athletes sustain sports injury if they train 'too much, too soon'. However, not all athletes are built the same; some can tolerate more training than others. It is for this reason that prescribing the same training programme to all athletes to reduce injury risk is not optimal from a coaching perspective. Rather, athletes require individualised training plans. In acknowledgement of athlete diversity, it is therefore essential to ask the right causal research question in studies examining sports injury aetiology. PURPOSE: In this first part of a British Journal of Sports Medicine educational series, we present four different causal research questions related to the 'too much, too soon' theory and critically discuss their relevance to sports injury prevention. CONTENT: If it is true that there is no 'one size fits all' training programme, then we need to consider by how much training can vary depending on individual athlete characteristics. To provide an evidence-base for subgroup-specific recommendations, a stronger emphasis on the following questions is needed: (1) How much training is 'too much' before athletes with different characteristics sustain sports-related injury? and (2) Does the risk of sports injury differ among athletes with a certain characteristic (eg, high experience) compared with athletes with other characteristics (eg, low experience) depending on how much training they perform? CONCLUSION: We recommend that sports injury researchers aiming to examine the 'too much, too soon' theory should carefully consider how they, assisted by coaches, athletes and clinicians, pose their causal research question. In the light of the limitations of population-based prevention that intends to provide all athletes with the same advice, we argue that a stronger emphasis on research questions targeting subgroups of athletes is needed. In doing so, researchers may assist athletes, clinicians and coaches to understand what training advice/programme works best, for whom and under what circumstances.