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Objectives: To investigate the underprescription of oral anticoagulation (OAC) in individual atrial fibrillation (AF) patients in primary care., Setting: Screening of patient records in 39 participating general practitioners (GPs) across the Netherlands., Participants: We screened 101 207 patient records identifying 2375 non-valvular AF patients., Methods: Using electronic patient files, we were able to screen the entire GP population for AF, CHA 2 DS 2 -VASc stroke risk scores, and the use of guidelines recommended OAC prescription. In case of a deviation from guidelines recommended OAC prescription, we checked the electronic patient file for any documented reason. Additionally, 6 weeks following the screening, we asked all GPs to provide information on any actions taken for the underprescribed patients., Results: We found a mean CHA 2 DS 2 -VASc score of 3.2. OAC prescription consisted of direct OAC in 1342/1984 (68%) and vitamin K-antagonists in the remainder of patients. OAC underprescription was present in 93/944 (9.9%) females and 101/1374 (9.7%) in males, respectively. In 111/146 (76.0%) of the underprescribed AF patients, no reason to withhold OAC was reported. Reported reasons to withhold OAC were patient refusal (n=10), cardiologist advice (n=7) and high risk of bleeding (n=7). Data regarding actions following the identification of OAC underprescription were available for 92/194 (47%) of the OAC underprescribed cases. After consultation OAC was initiated in 9/92 (10%) only., Conclusions: In this large Dutch study among GPs, we observed 9.8% underprescription of OAC in AF patients. In 76% of the AF patients lacking a prescription for OAC, no documentation for deviating from the guidelines was found. Only in a minority of cases detection of OAC underprescription lead to OAC initiation., Competing Interests: Competing interests: FV and MEWH have received honoraria for consulting and presentations from Boehringer-Ingelheim, Bayer Healthcare, BMS/Pfizer and Daiichi-Sankyo. Leonard Voorhout declares to have no conflict of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: Low-dose rivaroxaban has been indicated for the management of atherosclerotic cardiovascular disease (ASCVD) after recent (2019-2020) updates to European guidelines. We aimed to describe prescription trends of low-dose rivaroxaban in ASCVD patients over the period 2015-2022 in two European countries, to compare the trends before and after guideline changes, and to determine the characteristics of users., Methods: In a cross-sectional interrupted time series analysis, utilization of low-dose rivaroxaban (2.5 mg, twice daily) was measured in Clinical Practice Research Datalink Aurum (United Kingdom [UK]) and the PHARMO Database Network (the Netherlands) from 1 January 2015 to 28 February 2022 in patients with an ASCVD diagnosis. Incidence rates (IRs) and incidence rate ratios (IRRs) of new use (within 182 days) compared to the reference period, 2015-2018, were calculated. Age, sex and comorbidities of users were compared to those of nonusers., Results: In the UK, from 721 271 eligible subjects the IR of new use of low-dose rivaroxaban in the period 2015-2018, before guideline changes, was 12.4 per 100 000 person-years and after guideline changes in 2020-2022 was 124.0 (IRR 10.0, 95% confidence interval [CI] 8.5, 11.8). In the Netherlands from 394 851 subjects, the IR in 2015-2018 was 2.4 per 100 000 person-years and in 2020 was 16.3 (IRR 6.7, 95% CI 4.0, 11.4). Users were younger (UK mean difference [MD] -6.1 years, Netherlands -2.4 years; P < .05) and more likely to be male (UK difference 11.5%, Netherlands 13.4%; P < .001) than nonusers., Conclusions: There was a statistically significant increase in the use of low-dose rivaroxaban for the management of ASCVD after guideline changes in the UK and the Netherlands. There were international differences, but low-dose rivaroxaban has not been put into widespread practice., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Objective: Postmarketing observational studies report that a substantial percentage of patients with atrial fibrillation (AF) receive a reduced non-vitamin K antagonist oral anticoagulant (NOAC) dose without a clear indication. Recently, increasing evidence has become available to explore the clinical consequences of such off-label reduced dosing (OLRD). This study aims to systematically review and meta-analyse observational studies that report clinical outcomes associated with OLRD of NOACs compared with on-label non-reduced dosing (OLNRD) of NOACs in patients with AF., Methods and Analysis: We performed a systematic literature review and meta-analysis of observational studies reporting clinical outcomes in AF patients with OLRD of an NOAC compared with AF patients with OLNRD of an NOAC. Using random effects meta-analyses, we estimated the risk of stroke/thromboembolism, bleeding and all-cause mortality., Results: We included 19 studies with a total of 170 394 NOAC users. In these studies, the percentage of OLRD among patients with an indication for an on-label non-reduced NOAC dose ranged between 9% and 53%. 7 of these 19 studies met the predefined criteria for meta-analysis (n=80 725 patients). The pooled HR associated with OLRD of NOACs was 1.04 (95% CI 0.83 to 1.29; 95% prediction interval (PI) 0.60 to 1.79) for stroke/thromboembolism, 1.10 (95% CI 0.95 to 1.29; 95% PI 0.81 to 1.50) for bleeding and 1.22 (95% CI 0.81 to 1.84; 95% PI 0.55 to 2.70) for all-cause mortality., Conclusion: This meta-analysis shows no statistically significant increased risk of stroke/thromboembolism, nor a decreased bleeding risk, nor a difference in risk of all-cause mortality in patients with OLRD of NOACs. Future research may focus on differences between NOACs., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/. FR, MH and G-JG report unrestricted institutional grants for performing research in the field of atrial fibrillation from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer and Daiichi Sankyo. CBG reports personal fees from Bayer Healthcare and Boston Scientific; grants and personal fees from Boehringer-Ingelheim, BMS Pfizer and Janssen; and grants from Daiichi-Sankyo during the conduct of the study; personal fees from AbbVie, Espero, Medscape, Medtronic, Merck, the National Institutes of Health, Novo Nordisk, Roche, Rho Pharmaceuticals, CeleCor, Correvio, Philips, Abiomed and Anthos Therapeutics; grants from Akros, AstraZeneca, the US Food and Drug Administration, Glaxo Smith Kline, Medtronic Foundation and Apple; and grants and personal fees from Novartis and The Medicines Company outside the submitted work. SvD reports an unrestricted research grant from Stoffels Hornstra. All other authors (LJ, RvM, CJvdD and AWH) declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous 3 years; no other relationships or activities that could appear tohave influenced the submitted work., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Care groups organize integrated cardiovascular risk management programs in primary care for high risk patients. Results of long term cardiovascular risk management are scarce. The aim was to describe changes in low density lipoprotein cholesterol, systolic blood pressure and smoking between 2011 and 2018 in patients participating in an integrated program for cardiovascular risk management organized by a care group in the Netherlands., Aim: To explore whether long-term participation in an integrated cardiovascular risk management program could lead to the improvement of 3 important risk factors for cardiovascular disease., Methods: A protocol was developed for delegated practice nurse activities. A multidisciplinary data registry was used for uniform registration. The care group organized annual education for general practitioners and practice nurses on cardiovascular topics and regular meetings for practice nurses only to discuss complex patient cases and implementation issues. From 2015 onwards, the care group started with practice visitations to discuss performance and support practices with organizing integrated care., Results: In patients eligible for primary prevention as well as for secondary prevention similar trends were observed: lipid modifying and blood pressure lowering medication increased, mean low density lipoprotein cholesterol and mean systolic blood pressure decreased, patients on target for low density lipoprotein cholesterol and systolic blood pressure increased and the proportion of non-smokers with both low density lipoprotein cholesterol and systolic blood pressure on target increased. Improved registration between 2011 and 2013 was partly responsible for the sharp increase of patients on target for low density lipoprotein cholesterol and systolic blood pressure., Conclusion: In patients participating in an integrated cardiovascular risk management program, we saw annual improvements in 3 important cardiovascular risk factors between 2011 and 2018., (© 2023. The Author(s).)

Aim: To investigate the effects of off-label non-vitamin K oral anticoagulant (NOAC) dose reduction compared with on-label standard dosing in atrial fibrillation (AF) patients in routine care., Methods: Population-based cohort study using data from the United Kingdom Clinical Practice Research Datalink, comparing adults with non-valvular AF receiving an off-label reduced NOAC dose to patients receiving an on-label standard dose. Outcomes were ischaemic stroke, major/non-major bleeding and mortality. Inverse probability of treatment weighting and inverse probability of censoring weighting on the propensity score were applied to adjust for confounding and informative censoring., Results: Off-label dose reduction occurred in 2466 patients (8.0%), compared with 18 108 (58.5%) on-label standard-dose users. Median age was 80 years (interquartile range [IQR] 73.0-86.0) versus 72 years (IQR 66-78), respectively. Incidence rates were higher in the off-label dose reduction group compared to the on-label standard dose group, for ischaemic stroke (0.94 vs 0.70 per 100 person years), major bleeding (1.48 vs 0.83), non-major bleeding (6.78 vs 6.16) and mortality (10.12 vs 3.72). Adjusted analyses resulted in a hazard ratio of 0.95 (95% confidence interval [CI] 0.57-1.60) for ischaemic stroke, 0.88 (95% CI 0.57-1.35) for major bleeding, 0.81 (95% CI 0.67-0.98) for non-major bleeding and 1.34 (95% CI 1.12-1.61) for mortality., Conclusion: In this large population-based study, the hazards for ischaemic stroke and major bleeding were low, and similar in AF patients receiving an off-label reduced NOAC dose compared with on-label standard dose users, while non-major bleeding risk appeared to be lower and mortality risk higher. Caution towards prescribing an off-label reduced NOAC dose is therefore required., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background . Women with lower-extremity arterial disease (LEAD) are often underdiagnosed, present themselves with more advanced disease at diagnosis, and fare worse than men. Objective . To investigate to what extent potential gender differences exist in the frequency and reasons for general practitioner (GP) consultation six months prior to the diagnosis of LEAD, as potential indicators of diagnostic delay. Methods . Individuals older than 18 years diagnosed with LEAD, sampled from the Julius General Practitioner's Network (JGPN), were included and compared with a reference population, matched (1:2.6 ratio) in terms of age, sex, and general practice. We applied a zero-inflated negative binomial (ZINB) regression model. Results . The study population comprised 4044 patients with LEAD (43.5% women) and 10,486 subjects in the reference population (46.3% women). In the LEAD cohort, the number of GP contacts was 2.70 (95% CI: 2.42, 3.02) in women and 2.54 (2.29, 2.82) in men. In the reference cohort, 1.77 (95% CI: 1.62, 1.94) in women and 1.63 (95% CI: 1.50, 1.78) in men. In the LEAD cohort, 21.9% of GP contacts occurred one month prior to diagnosis. In both cohorts and both sexes, the most common cause of consultation during the last month before the index date was cardiovascular problems. Conclusions . Six months preceding the initial diagnosis of LEAD, patients visit the GP more often than a similar population without LEAD, regardless of gender. Reported gender differences in the severity of LEAD at diagnosis do not seem to be explained by a delay in presentation to the GP.

Aims: Optimize and assess the performance of an existing data mining algorithm for smoking status from hospital electronic health records (EHRs) in general practice EHRs., Methods and Results: We optimized an existing algorithm in a training set containing all clinical notes from 498 individuals (75 712 contact moments) from the Julius General Practitioners' Network (JGPN). Each moment was classified as either 'current smoker', 'former smoker', 'never smoker', or 'no information'. As a reference, we manually reviewed EHRs. Algorithm performance was assessed in an independent test set ( n  = 494, 78 129 moments) using precision, recall, and F1-score. Test set algorithm performance for 'current smoker' was precision 79.7%, recall 78.3%, and F1-score 0.79. For former smoker, it was precision 73.8%, recall 64.0%, and F1-score 0.69. For never smoker, it was precision 92.0%, recall 74.9%, and F1-score 0.83. On a patient level, performance for ever smoker (current and former smoker combined) was precision 87.9%, recall 94.7%, and F1-score 0.91. For never smoker, it was 98.0, 82.0, and 0.89%, respectively. We found a more narrative writing style in general practice than in hospital EHRs., Conclusion: Data mining can successfully retrieve smoking status information from general practice clinical notes with a good performance for classifying ever and never smokers. Differences between general practice and hospital EHRs call for optimization of data mining algorithms when applied beyond a primary development setting., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objectives: Cardiovascular conditions were shown to be predictive of clinical deterioration in hospitalised patients with coronavirus disease 2019 (COVID-19). Whether this also holds for outpatients managed in primary care is yet unknown. The aim of this study was to determine the incremental value of cardiovascular vulnerability in predicting the risk of hospital referral in primary care COVID-19 outpatients., Design: Analysis of anonymised routine care data extracted from electronic medical records from three large Dutch primary care registries., Setting: Primary care., Participants: Consecutive adult patients seen in primary care for COVID-19 symptoms in the 'first wave' of COVID-19 infections (March 1 2020 to June 1 2020) and in the 'second wave' (June 1 2020 to April 15 2021) in the Netherlands., Outcome Measures: A multivariable logistic regression model was fitted to predict hospital referral within 90 days after first COVID-19 consultation in primary care. Data from the 'first wave' was used for derivation (n = 5,475 patients). Age, sex, the interaction between age and sex, and the number of cardiovascular conditions and/or diabetes (0, 1, or ≥2) were pre-specified as candidate predictors. This full model was (i) compared to a simple model including only age and sex and its interaction, and (ii) externally validated in COVID-19 patients during the 'second wave' (n = 16,693)., Results: The full model performed better than the simple model (likelihood ratio test p<0.001). Older male patients with multiple cardiovascular conditions and/or diabetes had the highest predicted risk of hospital referral, reaching risks above 15-20%, whereas on average this risk was 5.1%. The temporally validated c-statistic was 0.747 (95%CI 0.729-0.764) and the model showed good calibration upon validation., Conclusions: For patients with COVID-19 symptoms managed in primary care, the risk of hospital referral was on average 5.1%. Older, male and cardiovascular vulnerable COVID-19 patients are more at risk for hospital referral., Competing Interests: The authors have declared that no competing interests exist.

Objective: To evaluate the differences in symptoms between men and women that present with lower limb peripheral artery disease (PAD)., Data Sources: Systematic review and meta-analysis using PubMed, EMBASE, and the Cochrane Library., Review Methods: A systematic search of the literature to identify studies that examined PAD and its symptoms using PubMed, EMBASE, and the Cochrane Library, which were screened in duplicate by two reviewers. Information on study design, source of data, population characteristics, and outcomes of interest was extracted and used the Newcastle-Ottawa Scale and Cochrane risk of bias tool. Quality of evidence was rated using the GRADE methodology. Estimates of relative effects were pooled to generate pooled odds ratios (OR) and their 95% confidence interval (CI) using a random effects model., Results: Thirteen cross sectional studies, six cohorts, one case control, and one randomised clinical trial, reporting on 1 929 966 patients with confirmed PAD (established by clinical history, clinical examination, and/or ankle brachial index, or further tests) were included. Women presented less often with intermittent claudication than men (25.9% vs. 30.2%) OR 0.78 (95% CI 0.72 - 0.84, very low quality of evidence), while rest pain and atypical leg symptoms were more prevalent in women (12.8% vs. 9.2%) OR 1.40 (95% CI 1.22 - 1.60, very low quality of evidence) and (22.8% vs. 19.8%) OR 1.18 (95% CI 0.96 - 1.45, very low quality of evidence), respectively., Conclusion: Women with PAD more often present with rest pain, while their prevalence of intermittent claudication is lower. They also tend to present more often with atypical leg symptoms. This study underlines that PAD symptom presentation differs between the sexes. Therefore, clinicians and researchers should not consider men and women as a single population and report their data separately., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: In the Netherlands, a digital decision support system for telephone triage at out-of-hours services in primary care (OHS-PC) is used. Differences in help-seeking behavior between men and women when transient ischemic attack (TIA) or stroke is suspected could potentially affect telephone triage and allocation of urgency. Aim: To assess patient and call characteristics and allocated urgencies between women and men who contacted OHS-PC with suspected TIA/stroke. Methods: A cross-sectional study of 1,266 telephone triage recordings of subjects with suspected neurological symptoms calling the OHS-PC between 2014 and 2016. The allocated urgencies were derived from the electronic medical records of the OHS-PC and the final diagnosis from the patient's own general practitioner, including diagnoses based on hospital specialist letters. Results: Five hundred forty-six men (mean age = 67.3 ± 17.1) and 720 women (mean age = 69.6 ± 19.5) were included. TIA/stroke was diagnosed in 294 men (54%) (mean age = 72.3 ± 13.6) and 366 women (51%) (mean age = 78.0 ± 13.8). In both genders, FAST (face-arm-speech test) symptoms were common in TIA/stroke (men 78%, women 82%) but also in no TIA/stroke (men 63%, women 62%). Men with TIA/stroke had shorter call durations than men without TIA/stroke (7.10 vs. 8.20 min, p = 0.001), whereas in women this difference was smaller and not significant (7.41 vs. 7.56 min, p = 0.41). Both genders were allocated high urgency in 75% of the final TIA/stroke cases. Conclusion: Overall, patient and call characteristics are mostly comparable between men and women, and these only modestly assist in identifying TIA/stroke. There were no gender differences in allocated urgencies after telephone triage in patients with TIA/stroke., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Exalto, van Doorn, Erkelens, Smit, Rutten, Kappelle and Zwart.)

Models of trait evolution form an important part of macroevolutionary biology. The Brownian motion model and Ornstein-Uhlenbeck models have become classic (null) models of character evolution, in which species evolve independently. Recently, models incorporating species interactions have been developed, particularly involving competition where abiotic factors pull species toward an optimal trait value and competitive interactions drive the trait values apart. However, these models assume a fitness function rather than derive it from population dynamics and they do not consider dynamics of the trait variance. Here, we develop a general coherent trait evolution framework where the fitness function is based on a model of population dynamics, and therefore it can, in principle, accommodate any type of species interaction. We illustrate our framework with a model of abundance-dependent competitive interactions against a macroevolutionary background encoded in a phylogenetic tree. We develop an inference tool based on Approximate Bayesian Computation and test it on simulated data (of traits at the tips). We find that inference performs well when the diversity predicted by the parameters equals the number of species in the phylogeny. We then fit the model to empirical data of baleen whale body lengths, using three different summary statistics, and compare it to a model without population dynamics and a model where competition depends on the total metabolic rate of the competitors. We show that the unweighted model performs best for the least informative summary statistic, while the model with competition weighted by the total metabolic rate fits the data slightly better than the other two models for the two more informative summary statistics. Regardless of the summary statistic used, the three models substantially differ in their predictions of the abundance distribution. Therefore, data on abundance distributions will allow us to better distinguish the models from one another, and infer the nature of species interactions. Thus, our framework provides a conceptual approach to reveal species interactions underlying trait evolution and identifies the data needed to do so in practice. [Approximate Bayesian computation; competition; phylogeny; population dynamics; simulations; species interaction; trait evolution.]., (© The Author(s) 2020. Published by Oxford University Press, on behalf of the Society of Systematic Biologists.)

Background  The benefit of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) on major bleeding was less prominent among atrial fibrillation (AF) patients with polypharmacy in post-hoc randomized controlled trials analyses. Whether this phenomenon also exists in routine care is unknown. The aim of the study is to investigate whether the number of concomitant drugs prescribed modifies safety and effectiveness of DOACs compared with VKAs in AF patients treated in general practice. Study Design  Adult, nonvalvular AF patients with a first DOAC or VKA prescription between January 2010 and July 2018 were included, using data from the United Kingdom Clinical Practice Research Datalink. Primary outcome was major bleeding, secondary outcomes included types of major bleeding, nonmajor bleeding, ischemic stroke, and all-cause mortality. Effect modification was assessed using Cox proportional hazard regression, stratified for the number of concomitant drugs into three strata (0-5, 6-8, ≥9 drugs), and by including the continuous variable in an interaction term with the exposure (DOAC vs. VKA). Results  A total of 63,600 patients with 146,059 person-years of follow-up were analyzed (39,840 person-years of DOAC follow-up). The median age was 76 years in both groups, the median number of concomitant drugs prescribed was 7. Overall, the hazard of major bleeding was similar between VKA-users and DOAC-users (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.87-1.11), though for apixaban a reduction in major bleeding was observed (HR 0.81; 95% CI 0.68-0.98). Risk of stroke was comparable, while risk of nonmajor bleeding was lower in DOAC users compared with VKA users (HR 0.92; 95% CI 0.88-0.97). We did not observe any evidence for an impact of polypharmacy on the relative risk of major bleeding between VKA and DOAC across our predefined three strata of concomitant drug use ( p -value for interaction = 0.65). For mortality, however, risk of mortality was highest among DOAC users, increasing with polypharmacy and independent of the type of DOAC prescribed ( p -value for interaction <0.01). Conclusion  In this large observational, population-wide study of AF patients, risk of bleeding, and ischemic stroke were comparable between DOACs and VKAs, irrespective of the number of concomitant drugs prescribed. In AF patients with increasing polypharmacy, our data appeared to suggest an unexplained yet increased risk of mortality in DOAC-treated patients, compared with VKA recipients., Competing Interests: Conflict of Interest None declared., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Background: It is recognised that medical tests are overused in primary care; however, it is unclear how best to reduce their use., Aim: To identify which strategies are effective in reducing the use of low-value medical tests in primary care settings., Design and Setting: Systematic review., Method: The databases MEDLINE, EMBASE, and Rx for Change were searched (January 1990 to November 2019) for randomised controlled trials (RCTs) that evaluated strategies to reduce the use of low-value medical tests in primary care settings. Two reviewers selected eligible RCTs, extracted data, and assessed their risk of bias., Results: Of the 16 RCTs included in the review, 11 reported a statistically significant reduction in the use of low-value medical tests. The median of the differences between the relative reductions in the intervention and control arms was 17% (interquartile range 12% to 24%). Strategies using reminders or audit/feedback showed larger reduction than those without these components (22% versus 14%, and 22% versus 13%, respectively) and patient-targeted strategies showed larger reductions than those not targeted at patients (51% versus 17%). Very few studies investigated the sustainability of the effect, adverse events, cost-effectiveness, or patient-reported outcomes related to reducing the use of low-value tests., Conclusion: This review indicates that it is possible to reduce the use of low-value medical tests in primary care, especially by using multiple components including reminders, audit/feedback, and patient-targeted interventions. To implement these strategies widely in primary care settings, more research is needed not only to investigate their effectiveness, but also to examine adverse events, cost-effectiveness, and patient-reported outcomes., (© British Journal of General Practice 2020.)

Background: A previous individual participant data (IPD) meta-analysis showed that the Wells rule and D-dimer testing cannot exclude suspected deep vein thrombosis (DVT) in cancer patients., Objectives: To explore reasons for this reduced diagnostic accuracy and to optimize the diagnostic pathway for cancer patients suspected of DVT., Patients and Methods: Using IPD from 13 studies in patients with suspected DVT, DVT prevalence and the predictive value of the Wells rule items and D-dimer testing were compared between patients with and without cancer. Next, we developed a prediction model with five variables selected from all available diagnostic predictors., Results: Among the 10 002 suspected DVT patients, there were 834 patients with cancer. The median prevalence of DVT in these patients with cancer was 37.5% (interquartile range [IQR], 30.8-45.5), whereas it was 15.1% (IQR, 11.5-16.7) in patients without cancer. Diagnostic performance of individual Wells rule items and D-dimer testing was similar across patients with and without cancer, except "immobility" and "history of DVT." The newly developed rule showed a pooled c-statistic 0.80 (95% confidence interval [CI], 0.75-0.83) and good calibration. However, using this model, still only 4.3% (95% CI, 3.0-5.7) of the suspected patients with cancer could be identified with a predicted DVT posttest probability of <2%., Conclusions: Likely because of the high prevalence of DVT, clinical models followed by D-dimer testing fail to rule out DVT efficiently in cancer patients suspected of DVT. Direct referral for compression ultrasonography appears to be the preferred approach for diagnosis of suspected DVT in cancer patients., (© 2020 International Society on Thrombosis and Haemostasis.)

Aims: To evaluate whether integrated care for atrial fibrillation (AF) can be safely orchestrated in primary care., Methods and Results: The ALL-IN trial was a cluster randomized, open-label, pragmatic non-inferiority trial performed in primary care practices in the Netherlands. We randomized 26 practices: 15 to the integrated care intervention and 11 to usual care. The integrated care intervention consisted of (i) quarterly AF check-ups by trained nurses in primary care, also focusing on possibly interfering comorbidities, (ii) monitoring of anticoagulation therapy in primary care, and finally (iii) easy-access availability of consultations from cardiologists and anticoagulation clinics. The primary endpoint was all-cause mortality during 2 years of follow-up. In the intervention arm, 527 out of 941 eligible AF patients aged ≥65 years provided informed consent to undergo the intervention. These 527 patients were compared with 713 AF patients in the control arm receiving usual care. Median age was 77 (interquartile range 72-83) years. The all-cause mortality rate was 3.5 per 100 patient-years in the intervention arm vs. 6.7 per 100 patient-years in the control arm [adjusted hazard ratio (HR) 0.55; 95% confidence interval (CI) 0.37-0.82]. For non-cardiovascular mortality, the adjusted HR was 0.47 (95% CI 0.27-0.82). For other adverse events, no statistically significant differences were observed., Conclusion: In this cluster randomized trial, integrated care for elderly AF patients in primary care showed a 45% reduction in all-cause mortality when compared with usual care., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with very limited therapeutic options. We have recently shown that the combined inhibition of EGFR and ROCK in TNBC cells results in cell death, however, the underlying mechanisms remain unclear. To investigate this, here we applied a mass spectrometry-based proteomic approach to identify proteins altered on single and combination treatments. Our proteomic data revealed autophagy as the major molecular mechanism implicated in the cells' response to combinatorial treatment. We here show that EGFR inhibition by gefitinib treatment alone induces autophagy, a cellular recycling process that acts as a cytoprotective response for TNBC cells. However, combined inhibition of EGFR and ROCK leads to autophagy blockade and accumulation of autophagic vacuoles. Our data show impaired autophagosome clearance as a likely cause of antitumor activity. We propose that the inhibition of the autophagic flux on combinatorial treatment is attributed to the major cytoskeletal changes induced on ROCK inhibition, given the essential role the cytoskeleton plays throughout the various steps of the autophagy process., (© 2020 Rontogianni et al.)

Introduction: Clinical guidelines recommend non-vitamin K antagonist oral anticoagulants (NOACs) over vitamin K antagonists (VKAs) for stroke prevention in most patients with atrial fibrillation (AF). Frail elderly were under-represented in the landmark NOAC-trials, leaving a knowledge gap on the optimal anticoagulant management (VKA or NOAC) in this increasing population. The aim of the Frail-AF (FRAIL-AF) study is to assess whether switching from international normalised ratio (INR)-guided VKA-management to a NOAC-based treatment strategy compared with continuing VKA-management is safe in frail elderly patients with AF., Methods and Analysis: The FRAIL-AF study is a pragmatic, multicentre, open-label, randomised controlled clinical trial. Frail elderly (age ≥75 years plus a Groningen Frailty Indicator score ≥3) who receive VKA-treatment for AF in the absence of a mechanical heart valve or severe mitral valve stenosis will be randomised to switch to a NOAC-based treatment strategy or to continue INR-guided VKA-management. Patients with severe renal impairment (estimated glomerular filtration rate <30 mL/min/1.73 m 2 ) will be excluded from randomisation. Based on existing trial evidence in non-frail patients, we will aim to explore whether NOAC-treatment is superior to VKA-therapy in reducing major or clinically relevant non-major bleeding events. Secondary outcomes include minor bleeding, the composite of ischaemic and haemorrhagic stroke, health-related quality of life and cost-effectiveness. The follow-up period for all subjects is 12 months., Ethics and Dissemination: The protocol was approved by the Medical Research Ethics Committee of the University Medical Center Utrecht, the Netherlands and by the Central Committee on Research Involving Human Subjects, the Netherlands. All patients are asked written informed consent. Results are expected in 2022 and will be disseminated through peer-reviewed journals as well as presentations at national and international conferences., Trial Registration Number: EudraCT: 2017-000393-11; The Netherlands Trial Registry: 6721 (FRAIL-AF study)., Competing Interests: Competing interests: G-JG and FHR report unrestricted institutional grants for performing research in the field of atrial fibrillation from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer and Daiichi Sankyo. MEWH reports personal fees from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer and Daiichi Sankyo, and grants from The Netherlands Organisation for Health Research and Development (ZonMw), outside the submitted work. MVH reports grants from The Netherlands Organisation for Health Research and Development (ZonMw), Dutch Healthcare Fund and grants and personal fees from Boehringer-Ingelheim, Bayer Healthcare, BMS Pfizer, Daiichi Sankyo and Aspen, outside the submitted work. All other authors (LPTJ, SvD, AWH, MCN, NMW, HLK, KCR, RMvdB and WFB) report no competing interests., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Direct oral anticoagulants (DOACs) are increasingly being prescribed for stroke prevention in patients with atrial fibrillation or for treating venous thromboembolism. In this short overview, we provide some guidance on possible differences between available DOACs as well as a comparison with traditional treatments using vitamin K antagonists. In the absence of head-to-head trials comparing different DOACs with each other, this is predominantly based on indirect meta-analysis and observational evidence. Thus, this should be interpreted with caution and considered as expert consensus.

Targeted therapies against oncogenic receptor tyrosine kinases (RTK) show promising results in the clinic. Unfortunately, despite the initial positive response, most patients develop therapeutic resistance. Most research has focused on acquired resistance occurring after an extensive time of treatment; however, the question remains as to how cells can survive an initial treatment, as early resistance to apoptosis will enable cells to develop any growth-stimulating mechanism. Here, the non-small cell lung cancer (NSCLC) PC9 cell line was used to systematically profile, by mass spectrometry, changes in the proteome, kinome, and phosphoproteome during early treatment with the EGFR inhibitor afatinib. Regardless of the response, initial drug-sensitive cells rapidly adapt to targeted therapy, and within days, cells regained the capacity to proliferate, despite persisting target inhibition. These data reveal a rapid reactivation of mTOR and MAPK signaling pathways after initial inhibition and an increase in abundance and activity of cytoskeleton and calcium signaling-related proteins. Pharmacologic inhibition of reactivated pathways resulted in increased afatinib efficacy. However more strikingly, cells that were restricted from accessing extracellular calcium were extremely sensitive to afatinib treatment. These findings were validated using three additional inhibitors tested in four different NSCLC cell lines, and the data clearly indicated a role for Ca 2+ signaling during the development of adaptive resistance. From a therapeutic point of view, the increased inhibitor efficacy could limit or even prevent further resistance development. Implications: Combined targeting of calcium signaling and RTKs may limit drug resistance and improve treatment efficacy. Mol Cancer Res; 16(11); 1773-84. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Objectives: Patients with atrial fibrillation (AF) are at increased risk of many adverse events, notably stroke. To prevent all adverse outcomes, integrated AF care is advocated though the potential domain for such multidisciplinary management is still unclear. Therefore, insight in the systemic nature of AF and identifying patients at risk of adverse events after oral anticoagulation is needed. The aim of this study is to first describe the risk of hospitalisation and mortality in community-dwelling older patients with AF using anticoagulants, and second to assess the association between traditional cardiac risk factors and these outcomes., Design: A prospective cohort., Setting: General practice., Participants: 2068 patients with AF using oral anticoagulants., Outcome Measures: We calculated incidence rates (IRs) of ischaemic stroke, bleeding, hospitalisations and mortality, and compared risk factors using Cox regression between those with and without an adverse event, both for cardiac and non-cardiac causes., Results: During a median follow-up of 2.7 (IQR 2.2-3.0) years, the IR per 100 person-years was 22.1 for hospitalisations and 6.7 for mortality. Non-cardiac events outnumbered cardiac events (IRs 15.7 vs 7.6 per 100 person-years for hospitalisation, p<0.001 and 5.0 vs 1.7, p<0.001 for mortality). As a comparison, the IRs for stroke and major bleeding were 1.7 and 0.8 per 100 person years, respectively. In multivariate models, high age, heart failure and vascular disease were independently associated with all-cause hospitalisation and- in addition to diabetes, previous stroke and renal disease-for all-cause mortality., Conclusions: In anticoagulated community-dwelling patients with AF, stroke risk is effectively reduced and thus fairly low, whereas risks of hospitalisation and mortality remain high, importantly mainly for non-cardiac causes. Notably high age, heart failure and vascular disease are predictive for such outcomes and may be of value in identifying high-risk patients in the future., Trial Registration Number: NTR3741., Competing Interests: Competing interests: G-JG and FHR received an unrestricted institutional grant from Boehringer Ingelheim. KGMM and G-JG received a grant from The Netherlands Organization for Scientific Research (ZONMW 918.10.615 and 91208004, and ZONMW 016.166.030). All funding sources had no role in the design, conduct, analyses or reporting of the study or in the decision to submit the manuscript for publication. All other authors declared no conflict of interest., (© Author(s) (or their employer(s)) 2018. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: Heart failure (HF) often coexists in atrial fibrillation (AF) but is frequently unrecognised due to overlapping symptomatology. Furthermore, AF can cause elevated natriuretic peptide levels, impairing its diagnostic value for HF detection. We aimed to assess the prevalence of previously unknown HF in community-dwelling patients with AF, and to determine the diagnostic value of the amino-terminal pro B-type natriuretic peptide (NTproBNP) for HF screening in patients with AF., Methods: Individual participant data from four HF-screening studies in older community-dwelling persons were combined. Presence or absence of HF was in each study established by an expert panel following the criteria of the European Society of Cardiology. We performed a two-stage patient-level meta-analysis to calculate traditional diagnostic indices., Results: Of the 1941 individuals included in the four studies, 196 (10.1%) had AF at baseline. HF was uncovered in 83 (43%) of these 196 patients with AF, versus 381 (19.7%) in those without AF at baseline. Median NTproBNP levels of patients with AF with and without HF were 744 pg/mL and 211 pg/mL, respectively. At the cut-point of 125 pg/mL, sensitivity was 93%, specificity 35%, and positive and negative predictive values 51% and 86%, respectively. Only 23% of all patients with AF had an NTproBNP level below the 125 pg/mL cut-point, with still a 13% prevalence of HF in this group., Conclusions: With a prevalence of nearly 50%, unrecognised HF is common among community-dwelling patients with AF. Given the high prior change, natriuretic peptides are diagnostically not helpful, and straightforward echocardiography seems to be the preferred strategy for HF screening in patients with AF., Competing Interests: Competing interests: G-JG is supported by a VENI grant from The Netherlands Organization for Scientific Research (ZONMW 016.166.030)., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The epidermal growth factor receptor (EGFR) represents one of the most common target proteins in anti-cancer therapy. To directly examine the structural and dynamical properties of EGFR activation by the epidermal growth factor (EGF) in native membranes, we have developed a solid-state nuclear magnetic resonance (ssNMR)-based approach supported by dynamic nuclear polarization (DNP). In contrast to previous crystallographic results, our experiments show that the ligand-free state of the extracellular domain (ECD) is highly dynamic, while the intracellular kinase domain (KD) is rigid. Ligand binding restricts the overall and local motion of EGFR domains, including the ECD and the C-terminal region. We propose that the reduction in conformational entropy of the ECD by ligand binding favors the cooperative binding required for receptor dimerization, causing allosteric activation of the intracellular tyrosine kinase., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Hypothesis-driven MS-based targeted proteomics has gained great popularity in a relatively short timespan. Next to the widely established selected reaction monitoring (SRM) workflow, data-independent acquisition (DIA), also referred to as sequential window acquisition of all theoretical spectra (SWATH) was introduced as a high-throughput targeted proteomics method. DIA facilitates increased proteome coverage, however, does not yet reach the sensitivity obtained with SRM. Therefore, a well-informed method selection is crucial for designing a successful targeted proteomics experiment. This is especially the case when targeting less conventional peptides such as those that contain PTMs, as these peptides do not always adhere to the optimal fragmentation considerations for targeted assays. Here, we provide insight into the performance of DIA, SRM, and MRM cubed (MRM(3) ) in the analysis of phosphorylation dynamics throughout the phosphoinositide 3-kinase mechanistic target of rapamycin (PI3K-mTOR) and mitogen-activated protein kinase (MAPK) signaling network. We observe indeed that DIA is less sensitive when compared to SRM, however demonstrates increased flexibility, by postanalysis selection of alternative phosphopeptide precursors. Additionally, we demonstrate the added benefit of MRM(3) , allowing the quantification of two poorly accessible phosphosites. In total, targeted proteomics enabled the quantification of 42 PI3K-mTOR and MAPK phosphosites, gaining a so far unachieved in-depth view mTOR signaling events linked to tyrosine kinase inhibitor resistance in non-small cell lung cancer., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: The effectiveness of colorectal cancer screening programs based on the fecal immunochemical test (FIT) is influenced by program adherence during consecutive screening rounds. We aimed to evaluate the participation rate, yield, and interval cancers in a third round of biennial CRC screening using FIT and to compare those with the first and the second screening round., Methods: A total of 3566 average-risk individuals aged 50-75 years were invited to participate in a third round of biennial FIT-based CRC screening. All FIT positives were recommended to undergo colonoscopy. We merged our data with the national cancer registry in the Netherlands to identify all non-screen-detected cancers in our cohort., Results: Of the invitees, 2142 (60%) returned the FIT in this third screening round, compared to 56% in the second round and 57% in the first round. Overall, 153 of the third-round participants (7.1%) had a positive FIT result, versus 7.9% in the second round and 8.1% in the first round (P=0.05). Of all FIT positives, 123 (80%) underwent colonoscopy. Within this group, 33 persons had advanced neoplasia. The predictive value of FIT positivity for advanced neoplasia was 27% (33/123), compared to 42% in the second round and 54% in the first round - a significant decline (P<0.01)., Conclusion: In an FIT-based screening program, participation rates remained stable over consecutive biennial screening rounds, while the FIT positivity rate and positive predictive value for advanced neoplasia gradually declined. Cancers in non-participants are significantly more advanced in staging than cancers in participants in the first round of screening., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: During colonoscopy, correct assessment of polyps is important. Recognition of early carcinomas is needed for tailor-made treatment and avoidance of unnecessary complications. Moreover, accurate diagnosis of diminutive lesions could result in a safe resect and discard strategy. We assessed the accuracy of polyp assessment by general endoscopists without specific training or experience in image-enhanced endoscopy during routine colonoscopies within a fecal immunochemical test (FIT)-based screening program., Methods: Data were collected in the third round of a FIT-based colorectal cancer screening pilot program. Patients diagnosed as FIT-positive (318) underwent colonoscopy using Olympus (160 and 180 series) endoscopes without magnification or routine use of (virtual) chromoendoscopy. Endoscopists received no special training. They made an on-site evaluation and classified detected polyps as hyperplastic, adenoma, carcinoma. Samples of resected lesions were sent for histopathology. Sensitivity and specificity were calculated. We differentiated for fellows and consultants., Results: In the 318 patients with a positive FIT-screening result, 683 lesions were detected; 564 lesions were included in the analyses. The pathologist classified these lesions as 141 hyperplastic polyps, 349 adenomas, 16 carcinomas, and 58 other. Sensitivity for diagnosis of adenomas was 88 % (95 %CI 84 - 91); specificity 49 % (95 %CI 42 - 55). Of the 16 colorectal carcinomas, endoscopists diagnosed four incorrectly (sensitivity 75 % [95 %CI 44 - 89]; specificity 99 % [95 %CI 98 - 100]), including three stage I cancers and one stage III cancer. There were no differences in accuracy of diagnosis that related to different sizes of lesions or the experience of the endoscopist., Conclusion: In a routine FIT-based screening setting and without specific training or routine use of (digital) chromoendoscopy, endoscopic prediction of the histopathology of colonic lesions is inaccurate when the procedure is performed by general endoscopists.

Several studies have shown high rates of psychopathology among female adolescents in detention. Although rates of mental health problems have been called alarming, it is unknown whether mental health needs in females in juvenile justice differ substantially from those of females in mental health care. Therefore, this study compared adolescent females in detention with inpatient adolescent females. For this purpose, a sample of 256 detained females (mean age 15.4 ± 1.3) was compared to 45 psychiatric inpatient females (mean age 15.8 ±1.4). Socio-demographic characteristics, mental health history and psychiatric problems were investigated using file-information and self-report questionnaires. Compared to detained females, inpatients more often showed internalizing problems and dissociation, whereas externalizing problems prevailed in girls in detention centers. Females in detention more often came from an ethnic minority group, while females in mental healthcare more often received mental healthcare previously and had parents with higher employment. This study confirms that mental health needs of girls in mental healthcare and in detention are high. However, non-mental health related factors were different as well - i.e. socio-economic factors - and are likely to influence the involvement with either service sector., (Copyright © 2011 Elsevier Ltd. All rights reserved.)