Risk of first-time major cardiovascular event among individuals with newly diagnosed type 2 diabetes: data from Danish registers.

AIMS/HYPOTHESIS: We aimed to examine whether individuals with initial omission of glucose-lowering drug treatment (GLDT), including those achieving initial remission of type 2 diabetes, may experience a higher risk of major adverse cardiovascular events (MACE) compared with well-controlled individuals on GLDT after a new type 2 diabetes diagnosis in real-world clinical practice. Furthermore, we examined whether a higher risk could be related to lower initiation of statins and renin-angiotensin system inhibitors (RASi). METHODS: In this cohort study, we used Danish registers to identify individuals with a first measured HbA1c between 48 and 57 mmol/mol (6.5-7.4%) from 2014 to 2020. Six months later, we divided participants into four groups according to GLDT and achieved HbA1c (<48 vs ≥48 mmol/mol [6.5%]): well-controlled and poorly controlled on GLDT; remission and persistent type 2 diabetes not on GLDT. We reported how much the standardised 5 year risk of MACE could be reduced for each group if initiation of statins and RASi was the same as in the well-controlled group on GLDT. RESULTS: We included 14,221 individuals. Compared with well-controlled participants on GLDT, the 5 year standardised risk of MACE was higher in the three other exposure groups: by 3.3% (95% CI 1.6, 5.1) in the persistent type 2 diabetes group not on GLDT; 2.0% (95% CI 0.4, 3.7) in the remission group not on GLDT; and 3.5% (95% CI 1.3, 5.7) in the poorly controlled group on GLDT. Fewer individuals not on GLDT initiated statins and RASi compared with individuals on GLDT. If initiation of statins and RASi had been the same as in the well-controlled group on GLDT, participants not on GLDT could have reduced their risk of MACE by 2.1% (95% CI 1.2, 2.9) in the persistent type 2 diabetes group and by 1.1% (95% CI 0.4, 1.9) in the remission group. CONCLUSIONS/INTERPRETATION: Compared with well-controlled individuals on GLDT, individuals not on initial GLDT had a higher 5 year risk of MACE, even among those achieving remission of type 2 diabetes. This may be related to lower use of statins and RASi.

Marginal structural models with monotonicity constraints: A case study in out-of-hospital cardiac arrest patients.

This paper deals with estimating the probability of a binary counterfactual outcome as a function of a continuous covariate under monotonicity constraints. We are motivated by the study of out-of-hospital cardiac arrest patients which aims to estimate the counterfactual 30-day survival probability if either all patients had received, or if none of the patients had received bystander cardiopulmonary resuscitation (CPR), as a function of the ambulance response time. It is natural to assume that the counterfactual 30-day survival probability cannot increase with increasing ambulance response time. We model the monotone relationship with a marginal structural model and B-splines. We then derive an estimating equation for the parameters of interest which however further relies on an auxiliary regression model for the observed 30-day survival probabilities. The predictions of the observed 30-day survival probabilities are used as pseudo-values for the unobserved counterfactual 30-day survival status. The methods are illustrated and contrasted with an unconstrained modeling approach in large-scale Danish registry data.

All-cause mortality among Danish nursing home residents before and during the COVID-19 pandemic: a nationwide cohort study.

A substantial part of mortality during the COVID-19-pandemic occurred among nursing home residents which caused alarm in many countries. We investigate nursing home mortality in relation to the expected mortality prior to the pandemic. This nationwide register-based study included all 135,501 Danish nursing home residents between 2015 until October 6, 2021. All-cause mortality rates were calculated using a standardization method on sex and age distribution of 2020. Survival probability and lifetime lost for 180 days was calculated using Kaplan Meier estimates. Of 3,587 COVID-19 related deaths, 1137 (32%) occurred among nursing home residents. The yearly all-cause mortality rates per 100,000 person-years in 2015, 2016, and 2017 were 35,301 (95% CI: 34,671-35,943), 34,801 (95% CI: 34,180-35,432), and 35,708 (95% CI: 35,085-36,343), respectively. Slightly elevated mortality rates per 100,000 person-years were seen in 2018, 2019, 2020, and 2021 of 38,268 (95% CI: 37,620-38,929), 36,956 (95% CI: 36,323-37,600), 37,475 (95% CI: 36,838-38,122), and 38,536 (95% CI: 37,798-39,287), respectively. For SARS-CoV-2-infected nursing home residents, lifetime lost difference was 42 days (95% CI: 38-46) in 2020 versus non-infected in 2018. Among vaccinated in 2021, lifetime lost difference was 25 days (95% CI: 18-32) for SARS-CoV-2-infected versus non-infected. Even though a high proportion of COVID-19 fatalities took place in nursing homes and SARS-CoV-2-infection increased the risk of individual death, the annual mortality was only slightly elevated. For future epidemics or pandemics reporting numbers of fatal cases in relation to expected mortality is critical.

The risk of healing complications in primary teeth with root fractures: A retrospective cohort study.

BACKGROUND/AIM: Primary teeth are frequently affected by traumatic dental injuries. Root fractures are rare and have a reported incidence of 2% in the primary dentition. Hence, there is limited evidence on this topic. This study aims to evaluate the risk of healing complications in primary teeth with root fracture and to identify possible sequelae in the permanent dentition following root fracture in the primary dentition. MATERIALS AND METHODS: A retrospective analysis of a cohort of 53 patients with 74 root fractured primary teeth. The standard follow-up program included clinical and radiographic examination after 4 weeks, 8 weeks, 6 months, and 1 year after the trauma and when the patient was 6 years of age. The following complications were registered: pulp necrosis (PN), pulp canal obliteration (PCO), ankylosis with replacement root resorption (ARR), infection-related root resorption (IRR), premature tooth loss (PTL), and repair-related resorption (RRR). STATISTICS: The Kaplan-Meier and Aalen-Johansen estimators were employed. The level of significance was 5%. RESULTS: A total of 74 teeth were included. 42 teeth were extracted at the initial examination. Risks estimated after 3 years: PTL 45.9% [95% CI: 28.8-63.0], PCO 12.9% [95% CI: 2.3-23.4], PN 14.9% [95% CI: 3.9-25.9], RRR 2.6% [95% CI: 0.0-7.5]. No teeth showed ARR or IRR. All complications were diagnosed within the first year. Most common sequelae in the permanent dentition was demarcated opacities, with an estimated risk of 20% [95% CI: 8.2-41.3]. CONCLUSIONS: There is a low risk of healing complications following a root fracture in the primary dentition. Root fractures often result in early extraction of the coronal fragment. The remaining apical fragment will undergo a physiological resorption. Aside from opacities, there is a low risk of sequelae in the permanent dentition.

Hypothetical interventions on emergency ambulance and prehospital acetylsalicylic acid administration in myocardial infarction patients presenting without chest pain.

BACKGROUND: Myocardial infarction (MI) patients presenting without chest pain are a diagnostic challenge. They receive suboptimal prehospital management and have high mortality. To elucidate potential benefits of improved management, we analysed expected outcome among non-chest pain MI patients if hypothetically they (1) received emergency ambulances/acetylsalicylic acid (ASA) as often as observed for chest pain patients, and (2) all received emergency ambulance/ASA. METHODS: We sampled calls to emergency and non-emergency medical services for patients hospitalized with MI within 24 h and categorized calls as chest pain/non-chest pain. Outcomes were 30-day mortality and a 1-year combined outcome of re-infarction, heart failure admission, and mortality. Targeted minimum loss-based estimation was used for all statistical analyses. RESULTS: Among 5418 calls regarding MI patients, 24% (1309) were recorded with non-chest pain. In total, 90% (3689/4109) of chest pain and 40% (525/1309) of non-chest pain patients received an emergency ambulance, and 73% (2668/3632) and 37% (192/518) of chest pain and non-chest pain patients received prehospital ASA. Providing ambulances to all non-chest pain patients was not associated with improved survival. Prehospital administration of ASA to all emergency ambulance transports of non-chest pain MI patients was expected to reduce 30-day mortality by 5.3% (CI 95%: [1.7%;9%]) from 12.8% to 7.4%. No significant reduction was found for the 1-year combined outcome (2.6% CI 95% [- 2.9%;8.1%]). In comparison, the observed 30-day mortality was 3% among ambulance-transported chest pain MI patients. CONCLUSIONS: Our study found large differences in the prehospital management of MI patients with and without chest pain. Improved prehospital ASA administration to non-chest pain MI patients could possibly reduce 30-day mortality, but long-term effects appear limited. Non-chest pain MI patients are difficult to identify prehospital and possible unintended effects of ASA might outweigh the potential benefits of improving the prehospital management. Future research should investigate ways to improve the prehospital recognition of MI in the absence of chest pain.

Perceived return-to-work pressure following cardiovascular disease is associated with age, sex, and diagnosis: a nationwide combined survey- and register-based cohort study.

BACKGROUND: Return to work is a key rehabilitation goal for people with cardiovascular disease (CVD) because employment matters to individuals and societies. However, people recovering from CVD often struggle with returning to work and maintaining employment. To identify people in need of vocational counselling, we examined the probability of feeling under pressure to return to work following CVD. METHODS: We conducted a combined survey- and register-based study in a randomly selected, population-based cohort of 10,000 people diagnosed with atrial fibrillation, heart failure, heart valve disease, or ischaemic heart disease in 2018. The questionnaire covered return-to-work items, and we reported the probabilities of feeling under pressure to return to work with 95% confidence intervals (CIs) in categories defined by sex, age, and CVD diagnosis. RESULTS: The survey response rate was 51.1%. In this study, we included 842 respondents (79.7% men) aged 32-85 years, who had returned to work following a sick leave. Overall, 249 (29.7%) had felt pressure to return to work. The probability of feeling under pressure to return to work ranged from 18.3% (95% CI: 13.1-24.6) among men aged > 55 years with atrial fibrillation to 51.7% (95% CI: 32.5-70.6) among women aged ≤ 55 years with atrial fibrillation. In addition, 66.0% of all respondents had not been offered vocational rehabilitation, and 48.6% of those who reported a need for vocational counselling had unmet needs. Survey responses also indicated that many respondents had returned to work before feeling mentally and physically ready. CONCLUSION: A substantial proportion of people with cardiovascular disease feel under pressure to return to work, and this pressure is associated with age, sex, and diagnosis. The results show that vocational rehabilitation must be improved and emphasize the importance of ensuring that cardiac rehabilitation programmes include all core rehabilitation components.

Human papillomavirus testing in metastatic squamous cell carcinoma of the neck with unknown primary using PCR on fine-needle aspiration smears: a prospective clinical study.

PURPOSE: Squamous cell carcinoma metastasis of the head and neck with unknown primary tumor (CUP) comprises a diagnostic challenge. Human papillomavirus (HPV) testing on cytologic specimens is gaining increasing focus as this may facilitate an early diagnosis of HPV-induced oropharyngeal carcinoma. This study aimed to prospectively assess PCR-based HPV-DNA testing on FNA smears in a clinical setting. METHODS: Patients referred to a tertiary Head and Neck Cancer Center with suspected CUP were included from November 2016 to November 2018. Scraped cell material from FNA smears was analyzed for HPV-DNA with PCR using general primers (GP5 + /GP6 +) and correlated with the origin and histology of the primary tumor (oropharynx vs. outside oropharynx or benign tumor). The turn-around time reflecting the workflow for HPV-DNA testing by PCR was also calculated. RESULTS: A total of 93 patients were enrolled in the study. The sensitivity and specificity were 86.7% [95% CI 75.4-94.1%] and 92.0% [95% CI 74.0-99.0%], and the positive and negative predictive values were 96.3% [95% CI 87.3-99.0%] and 74.2% [95% CI 59.9-84.7%], respectively. The turn-around time for HPV testing was a mean four calendar days. CONCLUSION: HPV-DNA testing on FNA smears can be performed within a reasonable timeframe and can guide for the detection of an HPV-positive oropharyngeal primary tumor in the clinical setting for patients presenting with CUP of the head and neck.

Impact of Male-Origin Microchimerism on Cardiovascular Disease in Women: A Prospective Cohort Study.

Increasing parity is associated with an increased risk of ischemic heart disease (IHD) and stroke in women. This is probably attributable to biological responses of pregnancy. Male cells of presumed fetal origin are commonly present in women years after pregnancy-a phenomenon termed male-origin microchimerism (MOM). In this study, we investigated whether MOM was associated with risk of IHD and ischemic stroke in women. We evaluated the association between MOM and ischemic events in a cohort of 766 Danish women enrolled in the Diet, Cancer and Health cohort during 1993-1997 when aged 50-64 years. Of these women, 545 (71.2%) tested positive for MOM through targeting of the Y chromosome (DYS14 DNA sequence) in their blood. Multiple Cox regression models were used to calculate hazard ratios with 95% confidence intervals. We found that MOM was associated with a significantly reduced rate of IHD (hazard ratio = 0.44, 95% confidence interval: 0.23, 0.83) but not ischemic stroke (hazard ratio = 0.80, 95% confidence interval: 0.46, 1.41). Our findings show that microchimerism positivity is associated with a lower rate of later IHD development in women. Although the underlying mechanisms are presently unknown, MOM may be relevant in women's cardiovascular health. More studies are needed to confirm these findings.

Sequential rank agreement methods for comparison of ranked lists.

The comparison of alternative rankings of a set of items is a general and common task in applied statistics. Predictor variables are ranked according to magnitude of association with an outcome, prediction models rank subjects according to the personalized risk of an event, and genetic studies rank genes according to their difference in gene expression levels. We propose a sequential rank agreement measure to quantify the rank agreement among two or more ordered lists. This measure has an intuitive interpretation, it can be applied to any number of lists even if some are partially incomplete, and it provides information about the agreement along the lists. The sequential rank agreement can be evaluated analytically or be compared graphically to a permutation based reference set in order to identify changes in the list agreements. The usefulness of this measure is illustrated using gene rankings, and using data from two Danish ovarian cancer studies where we assess the within and between agreement of different statistical classification methods.

P-wave indices as predictors of atrial fibrillation.

BACKGROUND: P-wave duration (PDURATION ) and P-wave area (PAREA ) have been linked to risk of atrial fibrillation (AF), but they do not improve the efficacy of Framingham AF risk score. We suggest the incorporation of both variables in one index, the P-wave area/P-wave duration (PAREA/DURATION ) index, which may be considered an expression of the average amplitude of the P wave that reflects aspects of P-wave morphology. OBJECTIVE: To assess the prognostic value of P-wave area/P-wave duration index (PAREA/DURATION index) in lead II together with other P-wave indices (PWIs) in incidence of AF in the Copenhagen Holter Study. METHODS: The study included 632 men and women, between 55 and 75 years with no apparent heart disease or AF. Baseline standard 12-lead Electrocardiography (ECGs) were analyzed manually. RESULTS: The median follow-up time was 14.7 (14.5;14.9) years. A total of 68 cases of AF and 233 cases of death were recorded. The restricted cubic spline method showed a U-shaped association between PAREA/DURATION and rate of AF. The lowest quintile of PAREA/DURATION index in lead II was associated with increased rate of AF, HR 2.80 (1.64-4.79). The addition of the new index to the Framingham model for AF improved the model in this population. The PAREA in lead II in its lowest quintile was also associated with increased rate of AF, HR 2.16 (1.25-3.75), but did not improve the Framingham model. PDURATION and P-wave terminal force (PTF) were not significantly associated with AF. CONCLUSION: A flat P wave as expressed by a small PAREA/DURATION index in lead II is associated with increased rate of incident AF beyond known AF risk factors.

Oral anticoagulation among atrial fibrillation patients with anaemia: an observational cohort study.

AIMS: To investigate the risk of stroke/thromboembolism (TE) and major bleeding associated with anaemia among patients with atrial fibrillation (AF). Also, to assess the effects of oral anticoagulation (OAC) and time in therapeutic range (TTR) with vitamin K antagonists according to level of haemoglobin (Hb). METHODS AND RESULTS: Through administrative registry databases, we identified all Danish patients diagnosed with AF from 1997 to 2012. We included 18 734 AF patients with recent available data on Hb. Multiple Cox regression analyses were used to estimate hazard ratios and to compute standardized absolute 1-year risks of stroke/TE and major bleeding. Among included patients, 3796 (20%) had mild anaemia (Hb 6.83-7.45 mmol/L for women and Hb 6.83-8.03 mmol/L for men) and 2562 (14%) had moderate/severe anaemia (Hb <6.83 mmol/L). Moderate/severe anaemia was associated with increased risk of major bleeding and 9.1% lower median TTR compared with no anaemia. Use of OAC was associated with reduced risk of stroke/TE among patients without anaemia [standardized absolute 1-year difference -2.5%, 95% confidence interval (CI) -3.8 to -1.7%] or with mild anaemia (-2.3%, 95% CI -2.8 to -1.8%), but not with moderate/severe anaemia, (0.03%, -1.8 to +2.8%, interaction P = 0.01). Oral anticoagulation was associated with a 5.3% (95% CI 2.1-8.7%) increased standardized absolute risk of major bleeding among AF patients with moderate/severe anaemia. CONCLUSION: Anaemia was common in patients with AF and associated with major bleeding and lower TTR. Oral anticoagulation was associated with more major bleeding, but no reduction in risk of stroke/TE among AF patients with moderate/severe anaemia.

Bystander cardiopulmonary resuscitation and long-term outcomes in out-of-hospital cardiac arrest according to location of arrest.

Aims: Bystander cardiopulmonary resuscitation (CPR) has increased in several countries following nationwide initiatives to facilitate bystander resuscitative efforts in out-of-hospital cardiac arrest (OHCA). We examined the importance of public or residential location of arrest on temporal changes in bystander CPR and outcomes. Methods and results: From the nationwide Danish Cardiac Arrest Registry, all OHCAs from 2001 to 2014 of presumed cardiac cause and between 18 and 100 years of age were identified. Arrests witnessed by emergency medical services personnel were excluded. Of 25 505 OHCAs, 26.4% (n = 6738) and 73.6% (n = 18 767) were in public and residential locations, respectively. Bystander CPR increased during 2001-2014 in both locations: from 36.4% [95% confidence interval (CI) 30.6-42.6%] to 83.1% (95% CI 80.0-85.8%) in public (P < 0.001) and from 16.0% (95% CI 13.2-19.3%) to 61.0% (95% CI 58.7-63.2%) in residential locations (P < 0.001). Concurrently, 30-day survival increased in public from 6.4% (95% CI 4.0-10.0%) to 25.2% (95% CI 22.1-28.7%) (P < 0.001), and in residential from 2.9% (95% CI 1.8-4.5%) to 10.0% (95% CI 8.7-11.4%) (P < 0.001). Among 2281 30-day survivors, 1-year risk of anoxic brain damage/nursing home admission during 2001-2014 decreased from 18.8% (95% CI 6.6-43.0%) to 6.8% (95% CI 3.9-11.8%) in public (P < 0.001), whereas the corresponding change was insignificant in residential locations from 11.8% (95% CI 3.3-34.3) to 17.6% (95% CI 12.7-23.9%) (P = 0.52). Conclusion: During 2001-2014, bystander CPR and 30-day survival more than doubled in both public and residential OHCA locations. A significant decrease in anoxic brain damage/nursing home admission was observed among 30-day survivors in public, but not among survivors from residential OHCAs.

On the estimation of average treatment effects with right-censored time to event outcome and competing risks.

We are interested in the estimation of average treatment effects based on right-censored data of an observational study. We focus on causal inference of differences between t-year absolute event risks in a situation with competing risks. We derive doubly robust estimation equations and implement estimators for the nuisance parameters based on working regression models for the outcome, censoring, and treatment distribution conditional on auxiliary baseline covariates. We use the functional delta method to show that these estimators are regular asymptotically linear estimators and estimate their variances based on estimates of their influence functions. In empirical studies, we assess the robustness of the estimators and the coverage of confidence intervals. The methods are further illustrated using data from a Danish registry study.

Risk factors for surgical intervention of early medical abortion.

BACKGROUND: By being noninvasive, medical termination of pregnancy has increased worldwide access to abortion and improved safety of unsafe abortion. However, secondary surgical intervention is the most frequent complication to medical abortion. OBJECTIVE: We aimed to identify and quantify risk factors for surgical intervention in women undergoing medically induced termination of pregnancy before 9 completed weeks of gestation. STUDY DESIGN: We conducted a nationwide cohort study, including all pregnancies terminated before 63 gestational days in women aged 15-49 years during the period 2005-2015. Induction regimen was 200 mg mifepristone followed 24-48 hours later by 0.8 mg vaginal misoprostol. All included pregnancies were followed up for 8 weeks from mifepristone administration. Data were retrieved from national health registers. Multiple logistic regression provided adjusted odds ratios of surgical intervention with 95% confidence intervals. The discriminative ability of the risk factors in identifying surgical intervention was assessed by cross-validated area under the receiver operating characteristic curve. RESULTS: Of 86,437 early medical abortions, 5320 (6.2%) underwent a surgical intervention within 8 weeks after induction. The proportion of surgical interventions increased from 3.5% in the 5th to 6th gestational week to 10.3% in week 9, odds ratio, 3.2 (95% confidence interval, 2.9-3.6). Compared with women aged 15-19 years, the risk of surgical intervention increased with increasing maternal age until the age of 30-34 years, odds ratio, 1.7 (95% confidence interval, 1.5-1.9), where after the risk decreased to an odds ratio for age group 40-49 of 1.2 (95% confidence interval, 1.0-1.4). Compared with nulliparous women, a history of only vaginal deliveries with spontaneous delivery of placenta implied an odds ratio of 1.1 (95% confidence interval, 1.0-1.2), women with a history of at least 1 cesarean delivery, an odds ratio of 1.5 (95% confidence interval, 1.3-1.6), and women having experienced a manual removal of placenta after a vaginal birth, an odds ratio of 2.0 (95% confidence interval, 1.7-2.4). Previous medically induced abortion decreased the risk of surgical intervention, odds ratio 0.84 (95% confidence interval, 0.78-0.91), whereas previous early (before 56 days of gestation) surgically induced abortion implied a 53% (95% confidence interval, 1.4-1.7) increased risk of surgical intervention. Previous surgical abortion after 55 days of gestation increased the risk by 17% (95% confidence interval, 1.1-1.3). The area under the receiver operating characteristic curve of the model including all quantified risk factors was 63% (95% confidence interval, 62-64%). CONCLUSION: Gestational age, maternal age, previous deliveries, and history of medically and surgically induced abortions all had a significant influence on the risk of surgical intervention of early medical abortion. However, inclusion of all quantified risk factors still left most interventions unpredictable.

Resumption of oral anticoagulation following traumatic injury and risk of stroke and bleeding in patients with atrial fibrillation: a nationwide cohort study.

Aims: We examined the risks of all-cause mortality, stroke, major bleeding, and recurrent traumatic injury associated with resumption of vitamin K antagonists (VKAs) and non-VKAs oral anticoagulants (NOACs) following traumatic injury in atrial fibrillation (AF) patients. Methods and results: This was a Danish nationwide registry-based study (2005-16), including 4541 oral anticoagulant (OAC)-treated AF patients experiencing traumatic injury (defined as traumatic brain injury, hip fracture, or traumatic torso or abdominal injury). Within 90 days following discharge from traumatic injury, 60.6% resumed VKA (median age = 80, CHA2DS2-VASc = 4, HAS-BLED = 2), 16.7% resumed NOAC (median age = 81, CHA2DS2-VASc = 4, HAS-BLED = 2), and 22.7% did not resume OAC treatment (median age = 81, CHA2DS2-VASc = 4, HAS-BLED = 3). Switch from VKA to NOAC occurred among 9.5%. Since 2009, the trend in OAC resumption increased (P-value <0.0001), in particular with NOACs (P-value <0.0001). Follow-up started 90 days after discharge, and time-varying multiple Cox regression analyses were used for comparisons. Compared with non-resumption, VKA and NOAC resumption were associated with lower hazard [95% confidence interval (CI)] of all-cause mortality [hazard ratio (HR) 0.48 (0.42-0.53) and HR 0.55 (0.47-0.66), respectively] and ischaemic stroke [HR 0.56 (0.43-0.72) and HR 0.54 (0.35-0.82), respectively], increased major bleeding hazard [HR 1.30 (1.03-1.64) and HR 1.15 (0.81-1.63), respectively], and similar hazard of recurrent traumatic injury [HR 0.93 (0.73-1.18) and HR 0.87 (0.60-1.27), respectively]. Conclusion: AF patients resuming VKA and NOAC treatment following traumatic injury have lower hazard of all-cause mortality and ischaemic stroke, increased hazard of major bleeding but without additional hazards of recurrent traumatic injury. Withholding OAC following a traumatic injury in AF patients may not be warranted.

External Validation and Optimization of the SPRING Model for Prediction of Survival After Surgical Treatment of Bone Metastases of the Extremities.

BACKGROUND: Survival predictions before surgery for metastatic bone disease in the extremities (based on statistical models and data of previous patients) are important for choosing an implant that will function for the remainder of the patient's life. The 2008-SPRING model, presented in 2016, enables the clinician to predict expected survival before surgery for metastatic bone disease in the extremities. However, to maximize the model's accuracy, it is necessary to maintain and update the patient database to refit the prediction models achieving more accurate calibration. QUESTIONS/PURPOSES: The purposes of this study were (1) to refit the 2008-SPRING model for prediction of survival before surgery for metastatic bone disease in the extremities with a more modern cohort; and (2) to evaluate the performance of the refitted SPRING model in a population-based cohort of patients having surgery for metastatic bone disease in the extremities. METHODS: We produced the 2013-SPRING model by adding to the 2008-SPRING model (n = 130) a cohort of patients from a consecutive institutional database of patients who underwent surgery for bone metastases in the extremities with bone resection and reconstruction between 2009 and 2013 at a highly specialized surgical center in Denmark (n = 140). Currently the model is only available as the nomogram fully available in the current article, which is sufficient to use in daily clinical work, but we are working on making the tool available online. As such, the 2013-SPRING model was produced using a consecutive cohort of patients (n = 270) treated during an 11-year period (2003-2013) called the training cohort, all treated with bone resection and reconstruction. We externally validated the 2008-SPRING and the 2013-SPRING models in a prospective cohort (n = 164) of patients who underwent surgery for metastatic bone disease in the extremities from May 2014 to May 2016, called the validation cohort. The validation cohort was identified from a cross-section of the Danish population who were treated for metastatic lesions (using endoprostheses and internal fixation) in the extremities at five secondary surgical centers and one highly specialized surgical center. This cross-section is representative of the Danish population and no patients were treated outside the included centers as a result of public healthcare settings. The indications for surgery for training and the validation cohort were pathologic fracture, impending fracture, or intractable pain despite radiation. Exact date of death was known for all patients as a result of the Danish Civil Registration System and no loss to followup existed. In the training cohort, 150 patients (out of 270 [56%]) and in the validation cohort 97 patients (out of 164 [59%]) died of disease within 1 year postoperatively. The 2013 model did not differ from the 2008 model and included hemoglobin, complete fracture/impending fracture, visceral and multiple bone metastases, Karnofsky Performance Status, and the American Society of Anesthesiologists score and primary cancer. The models were evaluated by area under the receiver operating characteristic curve (AUC ROC) and Brier score (the lower the better). RESULTS: The 2013-SPRING model was successfully refitted with a cohort using more patients than the 2008-SPRING model. Comparison of performance in external validation between the 2008 and 2013-SPRING models showed the AUC ROC was increased by 3% (95% confidence interval [CI], 0%-5%; p = 0.027) and 2% (95% CI, 0%-4%; p = 0.013) at 3-month and 6-month survival predictions, respectively, but not at 12 months at 1% (95% CI, 0%-3%; p = 0.112). Brier score was improved by -0.018 (95% CI, -0.032 to -0.004; p = 0.011) for 3-month, -0.028 (95% CI, -0.043 to -0.0123; p < 0.001) for 6-month, and -0.014 (95% CI, -0.025 to -0.002; p = 0.017) for 12-month survival prediction. CONCLUSIONS: We improved the SPRING model's ability to predict survival after surgery for metastatic bone disease in the extremities. As such, the refitted 2013-SPRING model gives the surgeon a tool to assist in the decision-making of a surgical implant that will serve the patient for the remainder of their life. The 2013-SPRING model may provide increased quality of life for patients with bone metastasis because potential implant failures can be minimized by precise survival prediction preoperatively and the model is freely available and ready to use from the current article. LEVEL OF EVIDENCE: Level I, diagnostic study.

Office blood pressure or ambulatory blood pressure for the prediction of cardiovascular events.

AIMS: To determine the added value of (i) 24-h ambulatory blood pressure relative to office blood pressure and (ii) night-time ambulatory blood pressure relative to daytime ambulatory blood pressure for 10-year person-specific absolute risks of fatal and non-fatal cardiovascular events. METHODS AND RESULTS: A total of 7927 participants were included from the International Database on Ambulatory blood pressure monitoring in relation to Cardiovascular Outcomes. We used cause-specific Cox regression to predict 10-year person-specific absolute risks of fatal and non-fatal cardiovascular events. Discrimination of 10-year outcomes was assessed by time-dependent area under the receiver operating characteristic curve (AUC). No differences in predicted risks were observed when comparing office blood pressure and ambulatory blood pressure. The median difference in 10-year risks (1st; 3rd quartile) was -0.01% (-0.3%; 0.1%) for cardiovascular mortality and -0.1% (-1.1%; 0.5%) for cardiovascular events. The difference in AUC (95% confidence interval) was 0.65% (0.22-1.08%) for cardiovascular mortality and 1.33% (0.83-1.84%) for cardiovascular events. Comparing daytime and night-time blood pressure, the median difference in 10-year risks was 0.002% (-0.1%; 0.1%) for cardiovascular mortality and -0.01% (-0.5%; 0.2%) for cardiovascular events. The difference in AUC was 0.10% (-0.08 to 0.29%) for cardiovascular mortality and 0.15% (-0.06 to 0.35%) for cardiovascular events. CONCLUSION: Ten-year predictions obtained from ambulatory blood pressure are similar to predictions from office blood pressure. Night-time blood pressure does not improve 10-year predictions obtained from daytime measurements. For an otherwise healthy population sufficient prognostic accuracy of cardiovascular risks can be achieved with office blood pressure.

Ischaemic and haemorrhagic stroke associated with non-vitamin K antagonist oral anticoagulants and warfarin use in patients with atrial fibrillation: a nationwide cohort study.

BACKGROUND: Non-vitamin K antagonist (VKA) oral anticoagulants (NOACs) are widely used as stroke prophylaxis in non-valvular atrial fibrillation (AF), but comparative data are sparse. PURPOSE: To compare dabigatran, rivaroxaban, and apixaban vs. VKA and the risk of stroke/thromboembolism (TE) and intracranial bleeding in AF. METHODS: Using Danish nationwide registries (2011-15), anticoagulant-naïve AF patients were identified when initiating VKA or an NOAC. Outcomes were stroke/TE and intracranial bleeding. Multiple outcome-specific Cox regression was performed to calculate average treatment effects as standardized differences in 1-year absolute risks. RESULTS: Overall, 43 299 AF patients initiated VKA (42%), dabigatran (29%), rivaroxaban (13%), and apixaban (16%). Mean CHA2DS2-VASc (SD) score was: VKA 2.9 (1.6), dabigatran 2.7 (1.6), rivaroxaban 3.0 (1.6), and apixaban 3.1 (1.6). Within patient-specific follow-up limited to the first 2 years, 1054 stroke/TE occurred and 261 intracranial bleedings. Standardized absolute risk (95% CI) of stroke/TE at 1 year after initiation of VKA was 2.01% (1.80% to 2.21%). In relation to VKA, the absolute risk differences were for dabigatran 0.11% (-0.16% to 0.42%), rivaroxaban 0.05% (-0.33% to 0.48%), and apixaban 0.45% (-0.001% to 0.93%). For the intracranial bleeding outcome, the standardized absolute risk at 1 year was for VKA 0.60% (0.49% to 0.72%); the corresponding absolute risk differences were for dabigatran -0.34% (-0.47% to - 0.21%), rivaroxaban -0.13% (-0.33% to 0.08%), and apixaban -0.20% (-0.38% to - 0.01%). CONCLUSIONS: Among anticoagulant-naïve AF patients, treatment with NOACs was not associated with significantly lower risk of stroke/TE compared with VKA, but intracranial bleeding risk was significantly lower with dabigatran and apixaban.

A critical assessment of early warning score records in 168,000 patients.

The national early warning score (NEWS) is recommended to detect deterioration in hospitalised patients. In 2013, a NEWS-based system was introduced in a hospital service with over 250,000 annual admissions, generating large amounts of NEWS data. The quality of such data has not been described. We critically assessed NEWS data recorded over 12 months. This observational study included NEWS records from adult inpatients hospitalized in the Capital Region of Denmark during 2014. Physiological variables and the use of supplementary oxygen (NEWS variables) were recorded. We identified implausible records and assessed the distributions of NEWS variable values. Of 2,835,331 NEWS records, 271,103 (10%) were incomplete with one or more variable missing and 0.2% of records containing implausible values. Digit preferences were identified for respiratory rate, supplementation oxygen flow, pulse rate, and systolic blood pressure. There was an accumulation of pulse rate records below 91 beats per minute. Among complete NEWS records, 64% had NEWS ≥ 1; 29% had NEWS ≥ 3; and 8% had NEWS ≥ 6. In a large set of NEWS data, 10% of the records were incomplete. In a system where data were manually entered into an electronic medical record, digit preferences and the accumulation of pulse rate records below 91 beats per minute, which is the limit for NEWS point generation, showed that staff practice influenced the recorded values. This indicates a potential limitation of transferability of research results obtained in such systems to fully automated systems.

Heart Team therapeutic decision-making and treatment in severe aortic valve stenosis.

Objectives After transcatheter aortic valve implantation (TAVI) has been available for high-risk patients with severe aortic valve stenosis (AVS), the decision-making of the Heart Team (HT) has not been examined. Design All adult patients with severe AVS referred to a large tertiary medical centre in 2011 were prospectively included. Multivariate regression analysis identified independent factors associated with treatment decisions. Results A total of 487 patients were included (mean age: 75 years, NYHA class III-IV: 47%). The HT proposed medical therapy (MT) in 35 (7%), TAVI in 60 (12%), and surgical aortic valve replacement (SAVR) in 392 (81%) of patients. In patients referred to intervention, TAVI compared with SAVR patients were older (OR = 1.17 per year, 95% CI 1.09-1.26; p < 0.01) with more previous coronary artery bypass surgery (OR = 385, 79-2738; p < 0.01), obesity (OR = 4.69, 1.51-13.77; p < 0.01), and chronic obstructive pulmonary disease (COPD) (OR = 3.66, 1.21-10.75; p = 0.02). MT patients compared with patients referred to any intervention were older, had a higher prevalence of COPD, peripheral arterial disease, previous myocardial infarction, and cerebrovascular disease. Conclusions The HT proposed intervention in 93% of patients with severe AVS despite high age, advanced symptoms and a high burden of co-morbidity. TAVI was reserved for older patients particularly with previous CABG.