Publications by authors named "Ewoud Schuit"

88 Publications

Can the mean linear energy transfer of organs be directly related to patient toxicities for current head and neck cancer intensity-modulated proton therapy practice?

Radiother Oncol 2021 Sep 14. Epub 2021 Sep 14.

Department of Radiation Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Background And Purpose: The relative biological effectiveness (RBE) of proton therapy is predicted to vary with the dose-weighted average linear energy transfer (LET). However, RBE values may substantially vary for different clinical endpoints. Therefore, the aim of this study was to assess the feasibility of relating mean D⋅LET parameters to patient toxicity for HNC patients treated with proton therapy.

Materials And Methods: The delivered physical dose (D) and the voxel-wise product of D and LET (D⋅LET) distributions were calculated for 100 head and neck cancer (HNC) proton therapy patients using our TPS (Raystation v6R). The means and covariance matrix of the accumulated D and D⋅LET of all relevant organs-at-risk (OARs) were used to simulate 2.500 data sets of different sizes. For each dataset, an attempt was made to add mean D⋅LET parameters to a multivariable NTCP model based on mean D parameters of the same OAR for xerostomia, tube feeding and dysphagia. The likelihood of creating an NTCP model with statistically significant parameters (i.e. power) was calculated as a function of the simulated sample size for various RBE models.

Results: The sample size required to have a power of at least 80% to show an independent effect of mean D⋅LET parameters on toxicity is over 15000 patients for all toxicities.

Conclusion: For current clinical practice, it is not feasible to directly model NTCP with both mean D and mean D⋅LET of OARs. These findings should not be interpreted as a contradiction of previous evidence for the relationship between RBE and LET.
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http://dx.doi.org/10.1016/j.radonc.2021.09.003DOI Listing
September 2021

A prognostic model, including quantitative fetal fibronectin, to predict preterm labour: the QUIDS meta-analysis and prospective cohort study.

Health Technol Assess 2021 09;25(52):1-168

Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, UK.

Background: The diagnosis of preterm labour is challenging. False-positive diagnoses are common and result in unnecessary, potentially harmful treatments (e.g. tocolytics, antenatal corticosteroids and magnesium sulphate) and costly hospital admissions. Measurement of fetal fibronectin in vaginal fluid is a biochemical test that can indicate impending preterm birth.

Objectives: To develop an externally validated prognostic model using quantitative fetal fibronectin concentration, in combination with clinical risk factors, for the prediction of spontaneous preterm birth and to assess its cost-effectiveness.

Design: The study comprised (1) a qualitative study to establish the decisional needs of pregnant women and their caregivers, (2) an individual participant data meta-analysis of existing studies to develop a prognostic model for spontaneous preterm birth within 7 days in women with symptoms of preterm labour based on quantitative fetal fibronectin and clinical risk factors, (3) external validation of the prognostic model in a prospective cohort study across 26 UK centres, (4) a model-based economic evaluation comparing the prognostic model with qualitative fetal fibronectin, and quantitative fetal fibronectin with cervical length measurement, in terms of cost per QALY gained and (5) a qualitative assessment of the acceptability of quantitative fetal fibronectin.

Data Sources/setting: The model was developed using data from five European prospective cohort studies of quantitative fetal fibronectin. The UK prospective cohort study was carried out across 26 UK centres.

Participants: Pregnant women at 22-34 weeks' gestation with signs and symptoms of preterm labour.

Health Technology Being Assessed: Quantitative fetal fibronectin.

Main Outcome Measures: Spontaneous preterm birth within 7 days.

Results: The individual participant data meta-analysis included 1783 women and 139 events of spontaneous preterm birth within 7 days (event rate 7.8%). The prognostic model that was developed included quantitative fetal fibronectin, smoking, ethnicity, nulliparity and multiple pregnancy. The model was externally validated in a cohort of 2837 women, with 83 events of spontaneous preterm birth within 7 days (event rate 2.93%), an area under the curve of 0.89 (95% confidence interval 0.84 to 0.93), a calibration slope of 1.22 and a Nagelkerke of 0.34. The economic analysis found that the prognostic model was cost-effective compared with using qualitative fetal fibronectin at a threshold for hospital admission and treatment of ≥ 2% risk of preterm birth within 7 days.

Limitations: The outcome proportion (spontaneous preterm birth within 7 days of test) was 2.9% in the validation study. This is in line with other studies, but having slightly fewer than 100 events is a limitation in model validation.

Conclusions: A prognostic model that included quantitative fetal fibronectin and clinical risk factors showed excellent performance in the prediction of spontaneous preterm birth within 7 days of test, was cost-effective and can be used to inform a decision support tool to help guide management decisions for women with threatened preterm labour.

Future Work: The prognostic model will be embedded in electronic maternity records and a mobile telephone application, enabling ongoing data collection for further refinement and validation of the model.

Study Registration: This study is registered as PROSPERO CRD42015027590 and Current Controlled Trials ISRCTN41598423.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 52. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25520DOI Listing
September 2021

The Influence of Severe Radiation-Induced Lymphopenia on Overall Survival in Solid Tumors: A Systematic Review and Meta-Analysis.

Int J Radiat Oncol Biol Phys 2021 Nov 28;111(4):936-948. Epub 2021 Jul 28.

Departments of Radiation Oncology.

Purpose: Emerging evidence suggests a detrimental prognostic association between radiation-induced lymphopenia (RIL) and pathologic response, progression-free survival, and overall survival (OS) in patients who undergo radiation therapy for cancer. The aim of this study was to systematically review and meta-analyze the prognostic impact of RIL on OS in patients with solid tumors.

Methods And Materials: PubMed/MEDLINE and Embase were systematically searched. The analysis included intervention and prognostic studies that reported on the prognostic relationship between RIL and survival in patients with solid tumors. An overall pooled adjusted hazard ratio (aHR) was calculated using a random-effects model. Subgroup analyses for different patient-, tumor-, treatment-, and study-related characteristics were performed using meta-regression.

Results: Pooling of 21 cohorts within 20 eligible studies demonstrated a statistically significant association between OS and grade ≥3 versus grade 0-2 RIL (n = 16; pooled aHR, 1.65; 95% confidence interval [CI], 1.43-1.90) and grade 4 RIL versus grade 0-3 (n = 5; aHR, 1.53; 95% CI, 1.24-1.90). Moderate heterogeneity among aHRs was observed, mostly attributable to overestimated aHRs in 7 studies likely subject to model-overfitting. Subgroup analysis showed significant prognostic impact of grade ≥3 RIL in 4 brain tumor (aHR, 1.63; 95% CI, 1.06-2.51), 4 lung cancer (aHR, 1.52; 95% CI, 1.01-2.29), and 3 pancreatic cancer (aHR, 1.92; 95% CI, 1.10-3.36) cohorts.

Conclusions: This meta-analysis demonstrates a significant detrimental prognostic association between grade ≥3 lymphopenia and OS in patients receiving radiation therapy for solid tumors. This finding appears consistent for tumors of the brain, thorax, and upper abdomen and provides an imperative to further elucidate the potential survival benefit of lymphopenia-mitigating strategies.
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http://dx.doi.org/10.1016/j.ijrobp.2021.07.1695DOI Listing
November 2021

Diagnostic accuracy of rapid antigen tests in asymptomatic and presymptomatic close contacts of individuals with confirmed SARS-CoV-2 infection: cross sectional study.

BMJ 2021 Jul 27;374:n1676. Epub 2021 Jul 27.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands

Objective: To assess the diagnostic test accuracy of two rapid antigen tests in asymptomatic and presymptomatic close contacts of people with SARS-CoV-2 infection on day 5 after exposure.

Design: Prospective cross sectional study.

Setting: Four public health service covid-19 test sites in the Netherlands.

Participants: 4274 consecutively included close contacts (identified through test-and-trace programme or contact tracing app) aged 16 years or older and asymptomatic for covid-19 when requesting a test.

Main Outcome Measures: Sensitivity, specificity, and positive and negative predictive values of Veritor System (Beckton Dickinson) and Biosensor (Roche Diagnostics) rapid antigen tests, with reverse-transcriptase polymerase chain reaction (RT-PCR) testing as reference standard. The viral load cut-off above which 95% of people with a positive RT-PCR test result were virus culture positive was used as a proxy of infectiousness.

Results: Of 2678 participants tested with Veritor, 233 (8.7%) had a RT-PCR confirmed SARS-CoV-2 infection of whom 149 were also detected by the rapid antigen test (sensitivity 63.9%, 95% confidence interval 57.4% to 70.1%). Of 1596 participants tested with Biosensor, 132 (8.3%) had a RT-PCR confirmed SARS-CoV-2 infection of whom 83 were detected by the rapid antigen test (sensitivity 62.9%, 54.0% to 71.1%). In those who were still asymptomatic at the time of sampling, sensitivity was 58.7% (51.1% to 66.0%) for Veritor (n=2317) and 59.4% (49.2% to 69.1%) for Biosensor (n=1414), and in those who developed symptoms were 84.2% (68.7% to 94.0%; n=219) for Veritor and 73.3% (54.1% to 87.7%; n=158) for Biosensor. When a viral load cut-off was applied for infectiouness (≥5.2 log10 SARS-CoV-2 E gene copies/mL), the overall sensitivity was 90.1% (84.2% to 94.4%) for Veritor and 86.8% (78.1% to 93.0%) for Biosensor, and 88.1% (80.5% to 93.5%) for Veritor and 85.1% (74.3% to 92.6%) for Biosensor, among those who remained asymptomatic throughout. Specificities were >99%, and positive and negative predictive values were >90% and >95%, for both rapid antigen tests in all analyses.

Conclusions: The sensitivities of both rapid antigen tests in asymptomatic and presymptomatic close contacts tested on day 5 onwards after close contact with an index case were more than 60%, increasing to more than 85% after a viral load cut-off was applied as a proxy for infectiousness.
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http://dx.doi.org/10.1136/bmj.n1676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8314145PMC
July 2021

National Protocol for Model-Based Selection for Proton Therapy in Head and Neck Cancer.

Int J Part Ther 2021 25;8(1):354-365. Epub 2021 Jun 25.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands.

In the Netherlands, the model-based approach is used to identify patients with head and neck cancer who may benefit most from proton therapy in terms of prevention of late radiation-induced side effects in comparison with photon therapy. To this purpose, a National Indication Protocol Proton therapy for Head and Neck Cancer patients (NIPP-HNC) was developed, which has been approved by the health care authorities. When patients qualify according to the guidelines of the NIPP-HNC, proton therapy is fully reimbursed. This article describes the procedures that were followed to develop this NIPP-HNC and provides all necessary information to introduce model-based selection for patients with head and neck cancer into routine clinical practice.
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http://dx.doi.org/10.14338/IJPT-20-00089.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270079PMC
June 2021

Development and validation of a risk prediction model of preterm birth for women with preterm labour symptoms (the QUIDS study): A prospective cohort study and individual participant data meta-analysis.

PLoS Med 2021 07 6;18(7):e1003686. Epub 2021 Jul 6.

Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.

Background: Timely interventions in women presenting with preterm labour can substantially improve health outcomes for preterm babies. However, establishing such a diagnosis is very challenging, as signs and symptoms of preterm labour are common and can be nonspecific. We aimed to develop and externally validate a risk prediction model using concentration of vaginal fluid fetal fibronectin (quantitative fFN), in combination with clinical risk factors, for the prediction of spontaneous preterm birth and assessed its cost-effectiveness.

Methods And Findings: Pregnant women included in the analyses were 22+0 to 34+6 weeks gestation with signs and symptoms of preterm labour. The primary outcome was spontaneous preterm birth within 7 days of quantitative fFN test. The risk prediction model was developed and internally validated in an individual participant data (IPD) meta-analysis of 5 European prospective cohort studies (2009 to 2016; 1,783 women; mean age 29.7 years; median BMI 24.8 kg/m2; 67.6% White; 11.7% smokers; 51.8% nulliparous; 10.4% with multiple pregnancy; 139 [7.8%] with spontaneous preterm birth within 7 days). The model was then externally validated in a prospective cohort study in 26 United Kingdom centres (2016 to 2018; 2,924 women; mean age 28.2 years; median BMI 25.4 kg/m2; 88.2% White; 21% smokers; 35.2% nulliparous; 3.5% with multiple pregnancy; 85 [2.9%] with spontaneous preterm birth within 7 days). The developed risk prediction model for spontaneous preterm birth within 7 days included quantitative fFN, current smoking, not White ethnicity, nulliparity, and multiple pregnancy. After internal validation, the optimism adjusted area under the curve was 0.89 (95% CI 0.86 to 0.92), and the optimism adjusted Nagelkerke R2 was 35% (95% CI 33% to 37%). On external validation in the prospective UK cohort population, the area under the curve was 0.89 (95% CI 0.84 to 0.94), and Nagelkerke R2 of 36% (95% CI: 34% to 38%). Recalibration of the model's intercept was required to ensure overall calibration-in-the-large. A calibration curve suggested close agreement between predicted and observed risks in the range of predictions 0% to 10%, but some miscalibration (underprediction) at higher risks (slope 1.24 (95% CI 1.23 to 1.26)). Despite any miscalibration, the net benefit of the model was higher than "treat all" or "treat none" strategies for thresholds up to about 15% risk. The economic analysis found the prognostic model was cost effective, compared to using qualitative fFN, at a threshold for hospital admission and treatment of ≥2% risk of preterm birth within 7 days. Study limitations include the limited number of participants who are not White and levels of missing data for certain variables in the development dataset.

Conclusions: In this study, we found that a risk prediction model including vaginal fFN concentration and clinical risk factors showed promising performance in the prediction of spontaneous preterm birth within 7 days of test and has potential to inform management decisions for women with threatened preterm labour. Further evaluation of the risk prediction model in clinical practice is required to determine whether the risk prediction model improves clinical outcomes if used in practice.

Trial Registration: The study was approved by the West of Scotland Research Ethics Committee (16/WS/0068). The study was registered with ISRCTN Registry (ISRCTN 41598423) and NIHR Portfolio (CPMS: 31277).
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http://dx.doi.org/10.1371/journal.pmed.1003686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8259998PMC
July 2021

Impact of radiation-induced toxicities on quality of life of patients treated for head and neck cancer.

Radiother Oncol 2021 07 20;160:47-53. Epub 2021 Apr 20.

Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, The Netherlands.

Purpose: The aim of this study is to establish the relative impact of physician-rated toxicities and patient-rated symptoms in head and neck cancer (HNC) on quality of life (QOL) and to weigh the various toxicities and symptoms during treatment plan optimization and selection.

Materials And Methods: This prospective cohort study comprised 1083 HNC patients (development: 750, validation: 333) treated with definitive radiotherapy with or without chemotherapy. Clinical factors were scored at baseline. Physician-rated and patient-rated outcome measures and QOL (EORTC QLQ-HN35 and QLQ-C30) were prospectively scored at baseline and 6, 12, 18 and 24 months after radiotherapy. The impact of 20 common toxicities and symptoms (related to swallowing, salivary function, speech, pain and general complaints) on QOL (0-100 scale) was established for each time point by combining principal component analysis and multivariable linear regression.

Results: Radiation-induced toxicities and symptoms resulted in a significant decline in QOL of patients with 12.4 ± 12.8 points at 6 months to 16.6 ± 17.1 points at 24 months. The multivariable linear models described the QOL points subtracted for each toxicity and symptom after radiotherapy. For example, xerostomia and weight loss had a significant but minor effect (on average -0.5 and -0.6 points) while speech problems and fatigue had a much greater impact (on average -11.9 and -17.4 points) on QOL. R goodness-of-fit values for the QOL models ranged from 0.64 (6 months) to 0.72 (24 months).

Conclusion: The relative impact of physician-rated toxicities and patient-rated symptoms on QOL was quantified and can be used to optimize, compare and select HNC radiotherapy treatment plans, to balance the relevance of toxicities and to achieve the best QOL for individual patients.
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http://dx.doi.org/10.1016/j.radonc.2021.04.011DOI Listing
July 2021

Prognostic Models Predicting Mortality in Preterm Infants: Systematic Review and Meta-analysis.

Pediatrics 2021 05;147(5)

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht and Utrecht University, Utrecht, Netherlands; and.

Context: Prediction models can be a valuable tool in performing risk assessment of mortality in preterm infants.

Objective: Summarizing prognostic models for predicting mortality in very preterm infants and assessing their quality.

Data Sources: Medline was searched for all articles (up to June 2020).

Study Selection: All developed or externally validated prognostic models for mortality prediction in liveborn infants born <32 weeks' gestation and/or <1500 g birth weight were included.

Data Extraction: Data were extracted by 2 independent authors. Risk of bias (ROB) and applicability assessment was performed by 2 independent authors using Prediction model Risk of Bias Assessment Tool.

Results: One hundred forty-two models from 35 studies reporting on model development and 112 models from 33 studies reporting on external validation were included. ROB assessment revealed high ROB in the majority of the models, most often because of inadequate (reporting of) analysis. Internal and external validation was lacking in 41% and 96% of these models. Meta-analyses revealed an average C-statistic of 0.88 (95% confidence interval [CI]: 0.83-0.91) for the Clinical Risk Index for Babies score, 0.87 (95% CI: 0.81-0.92) for the Clinical Risk Index for Babies II score, and 0.86 (95% CI: 0.78-0.92) for the Score for Neonatal Acute Physiology Perinatal Extension II score.

Limitations: Occasionally, an external validation study was included, but not the development study, because studies developed in the presurfactant era or general NICU population were excluded.

Conclusions: Instead of developing additional mortality prediction models for preterm infants, the emphasis should be shifted toward external validation and consecutive adaption of the existing prediction models.
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http://dx.doi.org/10.1542/peds.2020-020461DOI Listing
May 2021

Timing of recurrence after surgery in pelvic organ prolapse.

Int Urogynecol J 2021 Aug 17;32(8):2169-2176. Epub 2021 Mar 17.

Julius Center for Health sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Huispost Str. 6.131, PO Box 85500, 3508 GA, Utrecht, the Netherlands.

Objectives: The aim of this study was to determine when women are at risk for recurrent pelvic organ prolapse (POP).

Methods: From 2010 to 2018, all women with symptomatic prolapse, Pelvic Organ Prolapse Quantification (pop-Q) stage 2 in at least one compartment and prolapse surgery were included. The primary outcome measure was POP recurrence. Kaplan-Meier estimates were calculated, survival curves were created, and differences in survival curves were tested with log-rank test. Cox proportional hazard regression was used to investigate associations between recurrence and the number and type of involved compartment(s) and type of surgery.

Results: Forty-six (16.8%) out of 274 patients had POP recurrence during a mean follow-up time of 55 ± 32 months. The mean age was 64 ± 12 years. The hazard of recurrence increased the most in the first 2 years after POP surgery, flattened in years 3 and 4 and remained almost stable in the years thereafter, regardless of the site and number of involved compartment(s). The hazard of recurrence over time seemed the largest when all three compartments were involved. However, there was no statistically significant difference in recurrence between the numbers of (p = 0.65) or in the combination of involved compartments (p = 0.19). There was no difference in POP recurrence over time between prolapse repair with either sacrospinous ligament fixation or vaginal hysterectomy (p = 0.48).

Conclusions: Women are at the highest risk of POP recurrence in the first 2 years after POP surgery independent of the number or combination of involved compartment(s).
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http://dx.doi.org/10.1007/s00192-021-04754-6DOI Listing
August 2021

The Importance of Radiation Dose to the Atherosclerotic Plaque in the Left Anterior Descending Coronary Artery for Radiation-Induced Cardiac Toxicity of Breast Cancer Patients?

Int J Radiat Oncol Biol Phys 2021 08 10;110(5):1350-1359. Epub 2021 Mar 10.

Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address:

Purpose: Radiation-induced acute coronary events (ACEs) may occur as a treatment-related late adverse effect of breast cancer (BC) radiation. However, the underlying mechanisms behind this radiation-induced cardiac disease remain to be determined. The objective of this study was to test the hypothesis that radiation dose to calcified atherosclerotic plaques in the left anterior descending coronary artery (LAD) is a better predictor for ACEs than radiation dose to the whole heart or left ventricle in patients with BC treated with radiation therapy.

Methods And Materials: The study cohort consisted of 910 patients with BC treated with postoperative radiation therapy after breast-conserving surgery. In total, 163 patients had an atherosclerotic plaque in the LAD. The endpoint was the occurrence of an ACE after treatment. For each individual patient, the mean heart dose, volume of the left ventricle receiving ≥5 Gy (LV-V5), mean LAD dose, and mean dose to calcified atherosclerotic plaques in the LAD, if present, were acquired based on planning computed tomography scans. Cox regression analysis was used to analyze the effects on the cumulative incidence of ACEs.

Results: The median follow-up time was 9.2 years (range, 0.1-14.3 years). In total, 38 patients (4.2%) developed an ACE during follow-up. For patients with an atherosclerotic plaque (n = 163), the mean dose to the atherosclerotic plaque was the strongest predictor for ACEs, even after correction for cardiovascular risk factors (hazard ratio [HR], 1.269; 95% CI, 1.090-1.477; P = .002). The LV-V5 was associated with ACEs in patients without atherosclerotic plaques in the LAD (n = 680) (HR, 1.021; 95% CI, 1.003-1.039; P = .023).

Conclusions: The results of this study suggest that radiation dose to pre-existing calcified atherosclerotic plaques in the LAD is strongly associated with the development of ACEs in patients with BC.
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http://dx.doi.org/10.1016/j.ijrobp.2021.03.004DOI Listing
August 2021

Comprehensive toxicity risk profiling in radiation therapy for head and neck cancer: A new concept for individually optimised treatment.

Radiother Oncol 2021 04 3;157:147-154. Epub 2021 Feb 3.

Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, The Netherlands.

Background And Purpose: A comprehensive individual toxicity risk profile is needed to improve radiation treatment optimisation, minimising toxicity burden, in head and neck cancer (HNC) patients. We aimed to develop and externally validate NTCP models for various toxicities at multiple time points.

Materials And Methods: Using logistic regression, we determined the relationship between normal tissue irradiation and the risk of 22 toxicities at ten time points during and after treatment in 750 HNC patients. The toxicities involved swallowing, salivary, mucosal, speech, pain and general complaints. Studied predictors included patient, tumour and treatment characteristics and dose parameters of 28 organs. The resulting NTCP models were externally validated in 395 HNC patients.

Results: The NTCP models involved 14 organs that were associated with at least one toxicity. The oral cavity was the predominant organ, associated with 12 toxicities. Other important organs included the parotid and submandibular glands, buccal mucosa and swallowing muscles. In addition, baseline toxicity, treatment modality, and tumour site were common predictors of toxicity. The median discrimination performance (AUC) of the models was 0.71 (interquartile range: 0.68-0.75) at internal validation and 0.67 (interquartile range: 0.62-0.71) at external validation.

Conclusion: We established a comprehensive individual toxicity risk profile that provides essential insight into how radiation exposure of various organs translates into multiple acute and late toxicities. This comprehensive understanding of radiation-induced toxicities enables a new radiation treatment optimisation concept that balances multiple toxicity risks simultaneously and minimises the overall toxicity burden for an individual HNC patient who needs to undergo radiation treatment.
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http://dx.doi.org/10.1016/j.radonc.2021.01.024DOI Listing
April 2021

Placenta Pathology From Term Born Neonates With Normal or Adverse Outcome.

Pediatr Dev Pathol 2021 Mar-Apr;24(2):121-130. Epub 2021 Jan 20.

Department of Obstetrics, University Medical Center Utrecht, Utrecht, the Netherlands.

Background: The incidence of umbilical cord or placental parenchyma abnormalities associated with mortality or morbidity of term infants is lacking.

Methods: Placentas of 55 antepartum stillbirths (APD), 21 intrapartum stillbirths (IPD), 12 neonatal deaths (ND), and 80 admissions to a level 3 neonatal intensive care unit (NS) were studied and compared with 439 placentas from neonates from normal term pregnancies and normal outcome after vaginal delivery (NPVD) and with 105 placentas after an elective caesarian sections (NPEC).

Results: NPVD and NPEC placentas showed no or one abnormality in 70% and placentas from stillbirth showed two or more abnormalities in 80% of cases. APD placentas more frequently had a low weight and less formation of terminal villi. Hypercoiling was more often present in all study groups. Severe chronic villitis was almost exclusively present in APD placentas. Chorioamnionitis was significantly more frequent in APD, IPD and NS placentas and funisitis was more often observed in IPD and NS placentas.

Conclusion: Multiple placental abnormalities are significantly more frequent in placentas from term neonates with severe perinatal morbidity and mortality. These placental abnormalities are thought to be associated with disturbed oxygen transfer or with inflammation.
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http://dx.doi.org/10.1177/1093526620980608DOI Listing
January 2021

How can we build and maintain the resilience of our health care professionals during COVID-19? Recommendations based on a scoping review.

BMJ Open 2021 01 6;11(1):e043718. Epub 2021 Jan 6.

Nursing Science, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands.

Objective: To explore how to build and maintain the resilience of frontline healthcare professionals exposed to COVID-19 outbreak working conditions.

Design: Scoping review supplemented with expert interviews to validate the findings.

Setting: Hospitals.

Methods: We searched PubMed, Embase, PsycINFO, CINAHL, bioRxiv and medRxiv systematically and grey literature for articles focusing on the impact of COVID-19-like working conditions on the physical and/or mental health of healthcare professionals in a hospital setting. Articles using an empirical design about determinants or causes of physical and/or mental health and about interventions, measures and policies to preserve physical and/or mental health were included. Four experts were interviewed to reflect on the results from the scoping review.

Results: In total, 4471 records were screened leading to an inclusion of 73 articles. Recommendations prior to the outbreak fostering resilience included optimal provision of education and training, resilience training and interventions to create a feeling of being prepared. Recommendations during the outbreak consisted of (1) enhancing resilience by proper provision of information, psychosocial support and treatment (eg, create enabling conditions such as forming a psychosocial support team), monitoring the health status of professionals and using various forms and content of psychosocial support (eg, encouraging peer support, sharing and celebrating successes), (2) tasks and responsibilities, in which attention should be paid to kind of tasks, task mix and responsibilities as well as the intensity and weight of these tasks and (3) work patterns and working conditions. Findings of the review were validated by experts.

Conclusions: Recommendations were developed on how to build and maintain resilience of frontline healthcare professionals exposed to COVID-19 outbreak working conditions. These practical and easy to implement recommendations can be used by hospitals and other healthcare organisations to foster and preserve short-term and long-term physical and mental health and employability of their professionals.
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http://dx.doi.org/10.1136/bmjopen-2020-043718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7789206PMC
January 2021

Text-mining in electronic healthcare records can be used as efficient tool for screening and data collection in cardiovascular trials: a multicenter validation study.

J Clin Epidemiol 2021 04 25;132:97-105. Epub 2020 Nov 25.

Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Utrecht, the Netherlands; Department of Cardiology, Meander Medical Center, Amersfoort, the Netherlands; Dutch Network for Cardiovascular Research (WCN), Utrecht, the Netherlands.

Objective: This study aimed to validate trial patient eligibility screening and baseline data collection using text-mining in electronic healthcare records (EHRs), comparing the results to those of an international trial.

Study Design And Setting: In three medical centers with different EHR vendors, EHR-based text-mining was used to automatically screen patients for trial eligibility and extract baseline data on nineteen characteristics. First, the yield of screening with automated EHR text-mining search was compared with manual screening by research personnel. Second, the accuracy of extracted baseline data by EHR text mining was compared to manual data entry by research personnel.

Results: Of the 92,466 patients visiting the out-patient cardiology departments, 568 (0.6%) were enrolled in the trial during its recruitment period using manual screening methods. Automated EHR data screening of all patients showed that the number of patients needed to screen could be reduced by 73,863 (79.9%). The remaining 18,603 (20.1%) contained 458 of the actual participants (82.4% of participants). In trial participants, automated EHR text-mining missed a median of 2.8% (Interquartile range [IQR] across all variables 0.4-8.5%) of all data points compared to manually collected data. The overall accuracy of automatically extracted data was 88.0% (IQR 84.7-92.8%).

Conclusion: Automatically extracting data from EHRs using text-mining can be used to identify trial participants and to collect baseline information.
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http://dx.doi.org/10.1016/j.jclinepi.2020.11.014DOI Listing
April 2021

Prediction models for COVID-19 clinical decision making.

Lancet Digit Health 2020 10 22;2(10):e496-e497. Epub 2020 Sep 22.

Cochrane Netherlands, University Medical Center Utrecht, Utrecht University, Utrecht 3508 GA, Netherlands.

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http://dx.doi.org/10.1016/S2589-7500(20)30226-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7508517PMC
October 2020

An evaluation of the benefits and harms of antenatal corticosteroid treatment for women at risk of imminent preterm birth or prior to elective Caesarean-section: Study protocol for an individual participant data meta-analysis.

Wellcome Open Res 2020 25;5:38. Epub 2020 Feb 25.

Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK.

Antenatal corticosteroid treatment (ACT) has been widely accepted as a safe, beneficial treatment which improves outcomes following preterm birth. It has been shown to reduce respiratory distress syndrome and neonatal mortality and is commonly used in threatened or planned preterm delivery, as well as prior to elective Caesarean-section at term. There are some concerns however, that in some cases, ACT is used in patients where clinical benefit has not been established, or may potentially increase harm. Many women who receive ACT do not deliver preterm and the long-term consequences of ACT treatment are unclear. This study aims to evaluate the benefits and harms of ACT using latest trial evidence to allow refinement of current practice. This study will compare ACT with placebo or non-treatment. Inclusion criteria are: Randomised Controlled Trials (RCT) comparing ACT vs. no ACT (with or without placebo) in all settings. Exclusion criteria are: non-randomised or quasi-randomised studies and studies comparing single vs. multiple courses of ACT. Main outcomes are to evaluate, for women at risk of preterm birth or undergoing planned Caesarean- section, the benefits and harms of ACT, on maternal, fetal, newborn, and long-term offspring health outcomes. The individual participant data (IPD) of identified RCTs will be collected and consecutively synthesised using meta-analysis with both a one-stage model where all IPD is analysed together and a two-stage model where treatment effect estimates are calculated for each trial individually first and thereafter pooled in a meta-analysis. Sub-group analysis will be performed to identify heterogeneous effects of ACT across predefined risk groups. Co-opt is the Consortium for the Study of Pregnancy Treatments and aims to complete a robust evaluation of the benefits and harms of ACT. This IPD meta-analysis will contribute to this by allowing detailed interrogation of existing trial datasets. CRD42020167312 (03/02/2020).
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http://dx.doi.org/10.12688/wellcomeopenres.15661.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268149PMC
February 2020

Key challenges in normal tissue complication probability model development and validation: towards a comprehensive strategy.

Radiother Oncol 2020 07 23;148:151-156. Epub 2020 Apr 23.

Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, The Netherlands.

Normal Tissue Complication Probability (NTCP) models can be used for treatment plan optimisation and patient selection for emerging treatment techniques. We discuss and suggest methodological approaches to address key challenges in NTCP model development and validation, including: missing data, non-linear response relationships, multicollinearity between predictors, overfitting, generalisability and the prediction of multiple complication grades at multiple time points. The methodological approaches chosen are aimed to improve the accuracy, transparency and robustness of future NTCP-models. We demonstrate our methodological approaches using clinical data.
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http://dx.doi.org/10.1016/j.radonc.2020.04.012DOI Listing
July 2020

Prediction models for diagnosis and prognosis of covid-19: systematic review and critical appraisal

BMJ 2020 04 7;369:m1328. Epub 2020 Apr 7.

Department of Epidemiology, CAPHRI Care and Public Health Research Institute, Maastricht University, Peter Debyeplein 1, 6229 HA Maastricht, Netherlands

Objective: To review and appraise the validity and usefulness of published and preprint reports of prediction models for diagnosing coronavirus disease 2019 (covid-19) in patients with suspected infection, for prognosis of patients with covid-19, and for detecting people in the general population at increased risk of covid-19 infection or being admitted to hospital with the disease.

Design: Living systematic review and critical appraisal by the COVID-PRECISE (Precise Risk Estimation to optimise covid-19 Care for Infected or Suspected patients in diverse sEttings) group.

Data Sources: PubMed and Embase through Ovid, up to 1 July 2020, supplemented with arXiv, medRxiv, and bioRxiv up to 5 May 2020.

Study Selection: Studies that developed or validated a multivariable covid-19 related prediction model.

Data Extraction: At least two authors independently extracted data using the CHARMS (critical appraisal and data extraction for systematic reviews of prediction modelling studies) checklist; risk of bias was assessed using PROBAST (prediction model risk of bias assessment tool).

Results: 37 421 titles were screened, and 169 studies describing 232 prediction models were included. The review identified seven models for identifying people at risk in the general population; 118 diagnostic models for detecting covid-19 (75 were based on medical imaging, 10 to diagnose disease severity); and 107 prognostic models for predicting mortality risk, progression to severe disease, intensive care unit admission, ventilation, intubation, or length of hospital stay. The most frequent types of predictors included in the covid-19 prediction models are vital signs, age, comorbidities, and image features. Flu-like symptoms are frequently predictive in diagnostic models, while sex, C reactive protein, and lymphocyte counts are frequent prognostic factors. Reported C index estimates from the strongest form of validation available per model ranged from 0.71 to 0.99 in prediction models for the general population, from 0.65 to more than 0.99 in diagnostic models, and from 0.54 to 0.99 in prognostic models. All models were rated at high or unclear risk of bias, mostly because of non-representative selection of control patients, exclusion of patients who had not experienced the event of interest by the end of the study, high risk of model overfitting, and unclear reporting. Many models did not include a description of the target population (n=27, 12%) or care setting (n=75, 32%), and only 11 (5%) were externally validated by a calibration plot. The Jehi diagnostic model and the 4C mortality score were identified as promising models.

Conclusion: Prediction models for covid-19 are quickly entering the academic literature to support medical decision making at a time when they are urgently needed. This review indicates that almost all pubished prediction models are poorly reported, and at high risk of bias such that their reported predictive performance is probably optimistic. However, we have identified two (one diagnostic and one prognostic) promising models that should soon be validated in multiple cohorts, preferably through collaborative efforts and data sharing to also allow an investigation of the stability and heterogeneity in their performance across populations and settings. Details on all reviewed models are publicly available at https://www.covprecise.org/. Methodological guidance as provided in this paper should be followed because unreliable predictions could cause more harm than benefit in guiding clinical decisions. Finally, prediction model authors should adhere to the TRIPOD (transparent reporting of a multivariable prediction model for individual prognosis or diagnosis) reporting guideline.

Systematic Review Registration: Protocol https://osf.io/ehc47/, registration https://osf.io/wy245.

Readers' Note: This article is a living systematic review that will be updated to reflect emerging evidence. Updates may occur for up to two years from the date of original publication. This version is update 3 of the original article published on 7 April 2020 (BMJ 2020;369:m1328). Previous updates can be found as data supplements (https://www.bmj.com/content/369/bmj.m1328/related#datasupp). When citing this paper please consider adding the update number and date of access for clarity.
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http://dx.doi.org/10.1136/bmj.m1328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7222643PMC
April 2020

Replacing physical with virtual genetic tests: The importance of conscious methodological decisions.

Eur J Prev Cardiol 2020 10 10;27(15):1637-1638. Epub 2020 Mar 10.

Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, , the Netherlands.

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http://dx.doi.org/10.1177/2047487320904525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7549278PMC
October 2020

Study protocol for a randomised trial for atosiban versus placebo in threatened preterm birth: the APOSTEL 8 study.

BMJ Open 2019 11 26;9(11):e029101. Epub 2019 Nov 26.

Department of Obstetrics and Gynaecology, Amsterdam UMC, Location AMC, Amsterdam, The Netherlands

Introduction: Preterm birth complicates >15 million pregnancies annually worldwide. In many countries, women who present with signs of preterm labour are treated with tocolytics for 48 hours. Although this delays birth, it has never been shown to improve neonatal outcome. In 2015, the WHO stated that the use of tocolytics should be reconsidered and that large placebo-controlled studies to evaluate the effectiveness of tocolytics are urgently needed.

Methods And Analysis: We designed an international, multicentre, randomised, double-blinded, placebo-controlled clinical trial. Women with threatened preterm birth (gestational age 30-34 weeks), defined as uterine contractions with (1) a cervical length of < 15 mm or (2) a cervical length of 15-30 mm and a positive fibronectin test or (3) in centres where cervical length measurement is not part of the local protocol: a positive fibronectin test or insulin-like growth factor binding protein-1 (Actim-Partus test) or (4) ruptured membranes, will be randomly allocated to treatment with atosiban or placebo for 48 hours. The primary outcome is a composite of perinatal mortality and severe neonatal morbidity. Analysis will be by intention to treat. A sample size of 1514 participants (757 per group) will detect a reduction in adverse neonatal outcome from 10% to 6% (alpha 0.05, beta 0.2). A cost-effectiveness analysis will be performed from a societal perspective.

Ethics And Dissemination: This study has been approved by the Research Ethics Committee (REC) of the Amsterdam University Medical Centres, location AMC, as well as the REC's in Dublin and the UK. The results will be presented at conferences and published in a peer-reviewed journal. Participants will be informed about the results.

Trial Registration Number: Nederlands Trial Register (Trial NL6469).
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http://dx.doi.org/10.1136/bmjopen-2019-029101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887072PMC
November 2019

Prognostic models for adverse pregnancy outcomes in low-income and middle-income countries: a systematic review.

BMJ Glob Health 2019 30;4(5):e001759. Epub 2019 Oct 30.

Julius Global Health, Julius Center for Health Sciences and Primary Care, Universitair Medisch Centrum Utrecht, Utrecht University, Utrecht, The Netherlands.

Introduction: Ninety-nine per cent of all maternal and neonatal deaths occur in low-income and middle-income countries (LMIC). Prognostic models can provide standardised risk assessment to guide clinical management and can be vital to reduce and prevent maternal and perinatal mortality and morbidity. This review provides a comprehensive summary of prognostic models for adverse maternal and perinatal outcomes developed and/or validated in LMIC.

Methods: A systematic search in four databases (PubMed/Medline, EMBASE, Global Health Library and The Cochrane Library) was conducted from inception (1970) up to 2 May 2018. Risk of bias was assessed with the PROBAST tool and narratively summarised.

Results: 1741 articles were screened and 21 prognostic models identified. Seventeen models focused on maternal outcomes and four on perinatal outcomes, of which hypertensive disorders of pregnancy (n=9) and perinatal death including stillbirth (n=4) was most reported. Only one model was externally validated. Thirty different predictors were used to develop the models. Risk of bias varied across studies, with the item 'quality of analysis' performing the least.

Conclusion: Prognostic models can be easy to use, informative and low cost with great potential to improve maternal and neonatal health in LMIC settings. However, the number of prognostic models developed or validated in LMIC settings is low and mirrors the 10/90 gap in which only 10% of resources are dedicated to 90% of the global disease burden. External validation of existing models developed in both LMIC and high-income countries instead of developing new models should be encouraged.

Prospero Registration Number: CRD42017058044.
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http://dx.doi.org/10.1136/bmjgh-2019-001759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6830054PMC
October 2019

Inter- and intra-observer variability in fetal ductus venosus blood flow measurements in high-risk fetuses at 26-32 weeks.

Eur J Obstet Gynecol Reprod Biol 2019 Dec 22;243:67-71. Epub 2019 Oct 22.

Department of Obstetrics and Gynaecology, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Objectives: Early preterm fetal growth restriction is a significant contributor to perinatal morbidity and mortality. The ductus venosus pulsatility index for veins (DV PIV) is proposed as a monitoring tool because it appears to improve perinatal outcomes. The test characteristics and robustness of DV PIV have been inadequately described. The aim of this study was to investigate inter- and intra-observer variability of DV PIV.

Study Design: Nineteen women with a gestational age between 26 and 32 completed weeks were included in this study. Doppler sonographic fetal assessment was performed by two independent maternal-fetal medicine specialists. Each sonographer alternately performed three flow tracings for each participant, in the absence of the other sonographer (six tracings in total per patient). DV PIV was calculated automatically from stored tracings by a third researcher. Inter- and intra-observer variability of DV PIV and limits of agreement were assessed using the Bland-Altman method. Comparison of the distribution was performed with Kendall's related samples test, and the intraclass correlation coefficient (ICC) was calculated.

Results: In total, 114 DV measurements were taken from 19 participants with a median age of 31 years [interquartile range (IQR) 26-34 years] at a median gestational age of 28 weeks (IQR 27-29 weeks). The proportional limits of agreement for intra-observer variation were -0.48 to 0.48 and -0.39 to 0.62 for the two observers. ICCs were 0.66 [95% confidence interval (CI) 0.42-0.84] and 0.68 (95% CI 0.45-0.85). The proportional limits of agreement for inter-observer variation were -0.29 to 0.19 with an ICC of 0.89 (95% CI 0.73-0.96).

Conclusion: Inter-observer variation was far less than intra-observer variation, probably due to mitigation of biological variation by averaging three measurements. DV PIV has acceptable test characteristics for use in a clinical setting when the average of at least three consecutive measurements is used.
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http://dx.doi.org/10.1016/j.ejogrb.2019.10.028DOI Listing
December 2019

Multifactorial risk factors for mortality after chemotherapy and radiotherapy for non-small cell lung cancer.

Radiother Oncol 2020 11 20;152:117-125. Epub 2019 Sep 20.

KU Leuven - University of Leuven, Department of Oncology, Experimental Radiation Oncology, Leuven, Belgium; Maastricht University Medical Center, Department of Radiation Oncology (MAASTRO), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre+, The Netherlands.

Background And Purpose: A higher radiation dose to the heart is known to be associated with increased mortality in non-small cell lung cancer (NSCLC) patients. It is however unknown what the contribution of the heart dose is when other risk factors for mortality are also accounted for.

Materials And Methods: We constructed and externally validated prediction models of mortality after definitive chemoradiotherapy for NSCLC. Models were developed in 145 stage I-IIIB NSCLC patients. Clinical (performance status, age, gross tumour volume (GTV) combining primary tumour and involved lymph nodes, current smoker) and dosimetric (mean lung (MLD) and heart (MHD) dose) variables were considered. Multivariable logistic regression models predicting 12 and 24 month mortality were built in 5-fold cross-validation. Discrimination and calibration was assessed in 3 external validation datasets containing 878 (via distributed learning), 127 and 96 NSCLC patients.

Results: The best discriminating prediction models combined GTV, smoker and/or MHD: bootstrapping AUC (95% CI) of 0.74 (0.66-0.78) and 0.69 (0.55-0.74) at 12 and 24 months. At external validation, the 24 month mortality GTV-smoker-MHD model robustly showed moderate discrimination (AUC = 0.61-0.64 before and 0.64-0.65 after model update) with limited 0.01-0.07 improvement over a GTV-only model, and calibration slope (0.64-0.65). This model can identify patients for whom a MHD reduction may be useful (e.g. PPV = 77%, NPV = 52% (60% cut-off)).

Conclusions: Tumour volume is strongly related to mortality risk in the first 2 years after chemoradiotherapy for NSCLC. Modelling indicates that efforts to reduce cardiac dose may be relevant for small tumours and that smoking has an important negative association with survival.
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http://dx.doi.org/10.1016/j.radonc.2019.09.005DOI Listing
November 2020

A systematic breakdown of the levels of evidence supporting the European Society of Cardiology guidelines.

Eur J Prev Cardiol 2019 12 14;26(18):1944-1952. Epub 2019 Aug 14.

Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, The Netherlands.

Aims: Reviews of clinical practice guidelines have repeatedly concluded that only a minority of guideline recommendations are supported by high-quality evidence from randomised controlled trials. The aim of this study is to evaluate whether these findings apply to the whole cardiovascular evidence base or specific recommendation types and actions.

Methods: All recommendations from current European Society of Cardiology guidelines were extracted with their class (I, treatment is beneficial; II, treatment is possibly beneficial; III, treatment is harmful) and level of evidence (A, multiple randomised controlled trials/meta-analyses; B, single randomised controlled trials/large observational studies; C, expert opinion/small studies). Recommendations were categorised by type (therapeutic, diagnostic, other) and actions (e.g. pharmaceutical intervention/non-invasive imaging/test).

Results: In total, 3531 recommendations (median 128, interquartile range 108-150) were extracted from 27 guidelines. Therapeutic recommendations comprised 2545 (72.1%) recommendations, 411 (16.1%) were supported by level of evidence A, 833 (32.7%) by B and 1301 (51.1%) by C. Class I/III (should/should not) recommendations on minimally invasive interventions were most supported by level of evidence A (55/183, 30.1%) (B [70/183, 38.3%], C [58/183, 31.7%]), while class I/III recommendations on open surgical interventions were least supported by level of evidence A (15/164, 9.1%) (B [34/164, 20.7%], C [115/164, 70.1%]). Of all (831, 23.5%) diagnostic recommendations, just 44/503 (8.7%) class I/III recommendations were supported by level of evidence A (B (125/503, 24.9%), C (334/503, 66.4%)).

Conclusion: Evidence levels supporting European Society of Cardiology guideline recommendations differ widely between recommendation types and actions. Attributing to this variability are different evidence requirements, therapeutic/diagnostic recommendations, different feasibility levels for trials (e.g. open surgical/pharmacological) and many off-topic/policy recommendations based on expert opinion.
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http://dx.doi.org/10.1177/2047487319868540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6886117PMC
December 2019

Child outcomes after placement of a cervical pessary in women with a multiple pregnancy: A 4-year follow-up of the ProTWIN trial.

Acta Obstet Gynecol Scand 2019 10 18;98(10):1292-1300. Epub 2019 Jun 18.

Department of Obstetrics and Gynecology, Amsterdam UMC - Location AMC, Amsterdam, The Netherlands.

Introduction: The ProTWIN trial previously showed no beneficial effect of treatment with a cervical pessary vs usual care to prevent preterm birth in women with a multiple pregnancy. However, in women with a midtrimester short cervix (<38 mm), pessary did reduce the composite outcome of neonatal morbidity and mortality. This follow-up study evaluates the long-term outcomes of all children born to mothers who participated in the ProTWIN trial at 4 years of age.

Material And Methods: Parents received the Ages and Stages Questionnaire, Strength and Difficulties Questionnaire and a health questionnaire. All questionnaires were reported separately and as a combined outcome (abnormal child outcome). A linear mixed effects model was used to adjust for correlated data in twins and correction for confounders was performed. In exploratory analysis, a composite outcome of death or survival with abnormal child outcome was used by combining extrapolated data on child outcome with survival data. All data were analyzed for the total group and the subgroup of women with midtrimester short cervix.

Results: Of the original 813 women of the ProTWIN trial, we approached 579, of whom 258 participated (45%) in follow-up. We received questionnaires of 514 children (281 pessary vs 233 control), with 119 children in the subgroup of women with midtrimester short cervix. An abnormal child outcome was found in 23% in the pessary group vs 16% in the control group (odds ratio 1.58; 95% confidence interval 0.94-2.65). In exploratory analysis with extrapolated data on child outcome (n = 815), no difference in abnormal child outcome was seen between the pessary and control group. In the subgroup of women with a short cervix (n = 268), this composite outcome indicated a favorable outcome for children born to mothers with pessary.

Conclusions: In women with a multiple pregnancy, the use of a cervical pessary did not improve development, behavior or physical outcomes of the surviving children at age 4.
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http://dx.doi.org/10.1111/aogs.13630DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900136PMC
October 2019

Development and internal validation of a multinomial NTCP model for the severity of acute dyspnea after radiotherapy for lung cancer.

Radiother Oncol 2019 07 20;136:176-184. Epub 2019 Apr 20.

KU Leuven - University of Leuven, Department of Oncology, Experimental Radiation Oncology, Belgium; Maastricht University Medical Center, Department of Radiation Oncology (MAASTRO Clinic), GROW-School for Oncology and Developmental Biology, the Netherlands.

Background And Purpose: Dyspnea evolution after radiotherapy for lung cancer is complex with potential symptom deterioration and improvement from baseline. We developed and internally validated a multinomial normal tissue complication probability (NTCP) model predicting dyspnea grade.

Materials And Methods: Patient-reported dyspnea was collected pre-treatment and during 6 months follow-up for 182 stage I-IV lung cancer patients treated with radical (chemo)radiotherapy. Dyspnea changes (ΔDys) from the baseline grade (Dys) to the follow-up grade (Dys) were evaluated. A multinomial logistic regression model simultaneously predicting 3 grades of Dys (Dys ≥ 3, Dys = 2 and Dys ≤ 1 (reference level)) was optimized. Reference NTCP models predicting Dys ≥ 2 and Dys ≥ 3 risks irrespective of Dys were generated for comparison. Models were shrunken and performance was assessed using optimism-corrected AUC (bootstrapping).

Results: Rates of ΔDys ≥ 1 (deterioration) and ΔDys ≤ -1 (improvement) at 6 months were 31.9% and 12.6%. Dys ≥ 3, Dys = 2 and Dys ≤ 1 rates were 13.7%, 20.9% and 65.4%, respectively. The multinomial model (combining the risk factors Dys and MLD and the protective factor chemotherapy treatment) predicted Dys ≥ 3, Dys = 2 and Dys ≤ 1 with AUC (95% CI) of 0.72 (0.65-0.75) 0.76 (0.72-0.79) and 0.78 (0.74-0.80), respectively. Reference Dys ≥ 2 and Dys ≥ 3 models showed worse AUC: 0.64 (0.59-0.67) and 0.66 (0.50-0.70), respectively.

Conclusions: Dyspnea grade could be predicted with high accuracy using a multinomial NTCP model, yielding personalized dyspnea symptom improvement and deterioration risks.
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http://dx.doi.org/10.1016/j.radonc.2019.03.034DOI Listing
July 2019

Association of menopausal characteristics and risk of coronary heart disease: a pan-European case-cohort analysis.

Int J Epidemiol 2019 08;48(4):1275-1285

Department of Epidemiology, CIBER de Epidemiología y Salud Pública (CIBERESP),Madrid, Spain.

Background: Earlier age at menopause has been associated with increased risk of coronary heart disease (CHD), but the shape of association and role of established cardiovascular risk factors remain unclear. Therefore, we examined the associations between menopausal characteristics and CHD risk; the shape of the association between age at menopause and CHD risk; and the extent to which these associations are explained by established cardiovascular risk factors.

Methods: We used data from EPIC-CVD, a case-cohort study, which includes data from 23 centres from 10 European countries. We included only women, of whom 10 880 comprise the randomly selected sub-cohort, supplemented with 4522 cases outside the sub-cohort. We conducted Prentice-weighted Cox proportional hazards regressions with age as the underlying time scale, stratified by country and adjusted for relevant confounders.

Results: After confounder and intermediate adjustment, post-menopausal women were not at higher CHD risk compared with pre-menopausal women. Among post-menopausal women, earlier menopause was linearly associated with higher CHD risk [HRconfounder and intermediate adjusted per-year decrease = 1.02, 95% confidence interval (CI) = 1.01-1.03, p = 0.001]. Women with a surgical menopause were at higher risk of CHD compared with those with natural menopause (HRconfounder-adjusted = 1.25, 95% CI = 1.10-1.42, p < 0.001), but this attenuated after additional adjustment for age at menopause and intermediates (HR = 1.12, 95% CI = 0.96-1.29, p = 0.15). A proportion of the association was explained by cardiovascular risk factors.

Conclusions: Earlier and surgical menopause were associated with higher CHD risk. These associations could partially be explained by differences in conventional cardiovascular risk factors. These women might benefit from close monitoring of cardiovascular risk factors and disease.
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http://dx.doi.org/10.1093/ije/dyz016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6693816PMC
August 2019

Cardiac Function After Radiation Therapy for Breast Cancer.

Int J Radiat Oncol Biol Phys 2019 06 11;104(2):392-400. Epub 2019 Feb 11.

Department of Radiation Oncology, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands. Electronic address:

Purpose: The main purpose of this study was to test the hypothesis that incidental cardiac irradiation is associated with changes in cardiac function in breast cancer (BC) survivors treated with radiation therapy (RT).

Methods And Materials: We conducted a cross-sectional study consisting of 109 BC survivors treated with RT between 2005 and 2011. The endpoint was cardiac function, assessed by echocardiography. Systolic function was assessed with the left ventricular ejection fraction (LVEF) (n = 107) and the global longitudinal strain (GLS) of the left ventricle (LV) (n = 52). LV diastolic dysfunction (n = 109) was defined by e' at the lateral and septal region, which represents the relaxation velocity of the myocardium. The individual calculated RT dose parameters of the LV and coronary arteries were collected from 3-dimensional computed tomography-based planning data. Univariable and multivariable analysis using forward selection was performed to identify the best predictors of cardiac function. Robustness of selection was assessed using bootstrapping. The resulting multivariable linear regression model was presented for the endpoints of systolic and diastolic function.

Results: The median time between BC diagnosis and echocardiography was 7 years. No relation between RT dose parameters and LVEF was found. In the multivariable analysis for the endpoint GLS of the LV, the maximum dose to the left main coronary artery was most often selected across bootstrap samples. For decreased diastolic function, the most often selected model across bootstrap samples included age at time of BC diagnosis and hypertension at baseline. Cardiac dose-volume histogram parameters were less frequently selected for this endpoint.

Conclusions: This study shows an association between individual cardiac dose distributions and GLS of the LV after RT for BC. No relation between RT dose parameters and LVEF was found. Diastolic function was most associated with age and hypertension at time of BC diagnosis. Further research is needed to make definitive conclusions.
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http://dx.doi.org/10.1016/j.ijrobp.2019.02.003DOI Listing
June 2019

Smoking Cessation Pharmacotherapy Based on Genetically-Informed Biomarkers: What is the Evidence?

Nicotine Tob Res 2019 08;21(9):1289-1293

Meta-Research Innovation Center at Stanford (METRICS), Stanford University, Stanford, CA.

Introduction: Pharmacogenomic studies have used genetic variants to identify smokers likely to respond to pharmacological treatments for smoking cessation.

Methods: We performed a systematic review and meta-analysis of primary and secondary analyses of trials of smoking cessation pharmacotherapies. Eligible were trials with data on a priori selected single nucleotide polymorphisms, replicated non-single nucleotide polymorphisms, and/or the nicotine metabolite ratio. We estimated the genotype × treatment interaction as the ratio of risk ratios (RRR) for treatment effects across genotype groups.

Results: We identified 18 trials (N = 9017 participants), including 40 active (bupropion, nicotine replacement therapy [NRT], varenicline, or combination therapies) versus placebo comparisons and 16 active versus active comparisons. There was statistical evidence of heterogeneity across rs16969968 genotypes in CHRNA5 with regard to both 6-month abstinence and end-of-treatment abstinence in non-Hispanic black smokers and end-of-treatment abstinence in non-Hispanic white smokers. There was also heterogeneity across rs1051730 genotypes in CHRNA3 with regard to end-of-treatment abstinence in non-Hispanic white smokers. There was no clear statistical evidence for other genotype-by-treatment combinations. Compared with placebo, NRT was more effective among non-Hispanic black smokers with rs16969968-GG with regard to both 6-month abstinence (RRR for GG vs. GA or AA, 3.51; 95% confidence interval [CI] = 1.19 to 10.30) and end-of-treatment abstinence (RRR for GG vs. GA or AA, 5.84; 95% CI = 1.89 to 18.10). Among non-Hispanic white smokers, NRT effectiveness relative to placebo was comparable across rs1051730 and rs169969960 genotypes.

Conclusions: We did not identify widespread differential effects of smoking cessation pharmacotherapies based on genotype. The quality of the evidence is generally moderate.

Implications: Although we identified some evidence of genotype × treatment interactions, the vast majority of analyses did not provide evidence of differential treatment response by genotype. Where we find some evidence, these results should be considered preliminary and interpreted with caution because of the small number of contributing trials per genotype comparison, the wide confidence intervals, and the moderate quality of evidence. Prospective trials and individual-patient data meta-analyses accounting for heterogeneity of treatment effects through modeling are needed to assess the clinical utility of genetically informed biomarkers to guide pharmacotherapy choice for smoking cessation.
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http://dx.doi.org/10.1093/ntr/ntz009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6698953PMC
August 2019
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