Publications by authors named "Joanna IntHout"

75 Publications

Predicting personalised absolute treatment effects in individual participant data meta-analysis: An introduction to splines.

Res Synth Methods 2022 Jan 9. Epub 2022 Jan 9.

Health Evidence, Radboud University Medical Center, Nijmegen, The Netherlands.

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http://dx.doi.org/10.1002/jrsm.1546DOI Listing
January 2022

Cancer worry among BRCA1/2 pathogenic variant carriers choosing surgery to prevent tubal/ovarian cancer: course over time and associated factors.

Support Care Cancer 2022 Jan 8. Epub 2022 Jan 8.

Department of Obstetrics and Gynaecology, Radboud Institute for Health Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands.

Objective: High cancer risks, as applicable to BRCA1 and BRCA2 pathogenic variant (PV) carriers, can induce significant cancer concerns. We examined the degree of cancer worry and the course of this worry among BRCA1/2-PV carriers undergoing surgery to prevent ovarian cancer, and identified factors associated with high cancer worry.

Methods: Cancer worry was evaluated as part of the multicentre, prospective TUBA-study (NCT02321228) in which BRCA1/2-PV carriers choose either novel risk-reducing salpingectomy with delayed oophorectomy or standard risk-reducing salpingo-oophorectomy. The Cancer Worry Scale was obtained before and 3 and 12 months after surgery. Cancer worry patterns were analysed using latent class growth analysis and associated factors were identified with regression analysis.

Results: Of all 577 BRCA1/2-PV carriers, 320 (57%) had high (≥ 14) cancer worry pre-surgery, and 54% had lower worry 12 months post-surgery than pre-surgery. Based on patterns over time, BRCA1/2-PV carriers could be classified into three groups: persistently low cancer worry (56%), persistently high cancer worry (6%), and fluctuating, mostly declining, cancer worry (37%). Factors associated with persistently high cancer concerns were age below 35 (BRCA1) or 40 (BRCA2), unemployment, previous breast cancer, lower education and a more recent BRCA1/2-PV diagnosis.

Conclusions: Some degree of cancer worry is considered normal, and most BRCA1/2-PV carriers have declining cancer worry after gynaecological risk-reducing surgery. However, a subset of these BRCA1/2-PV carriers has persisting major cancer concerns up to 1 year after surgery. They should be identified and potentially offered additional support.

Clinical Trial Registration: The TUBA-study is registered at ClinicalTrials.gov since December 11th, 2014. Registration number: NCT02321228.
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http://dx.doi.org/10.1007/s00520-021-06726-4DOI Listing
January 2022

Effects of a Personal Health Record in Maternity Care: A Stepped-Wedge Trial.

Int J Environ Res Public Health 2021 09 30;18(19). Epub 2021 Sep 30.

Department of Obstetrics and Gynaecology, Radboud University Medical Center, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands.

To improve both the active involvement of pregnant women in their maternal health and multidisciplinary collaboration between maternal care professionals, we introduced a personal health record (PHR) in routine maternity care. We studied the effects of this intervention on the percentage of uncomplicated births, women's perspectives on quality of care, and the collaboration between health care professionals. We performed a stepped-wedge cluster randomized controlled trial with four clusters and 13 maternity health centers (community-based midwife practices and hospitals) in one collaborative area. In total, 7350 pregnant women and 220 health care professionals participated. Uncomplicated births accounted for 51.8% (95% CI 50.1-53.9%) of total births in the control group and 55.0% (CI 53.5-56.5%) of total births in the intervention group ( = 0.289). Estimated means revealed that the differences detected in the stepped-wedge study were due to time and not the intervention. Women's perspectives on quality of care and collaboration between health care professionals revealed no relevant differences between the control and intervention groups. The introduction of the PHR resulted in no significant effect on the chosen measures of quality of maternal care. The suggested positive effect in the raw data was a local trend which was less visible in the national database, and thus might be related to subtle changes toward an improved collaborative culture in the study region.
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http://dx.doi.org/10.3390/ijerph181910343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508495PMC
September 2021

Early prediction of post-molar gestational trophoblastic neoplasia and resistance to methotrexate, based on a single serum human chorionic gonadotropin measurement.

Gynecol Oncol 2021 12 30;163(3):531-537. Epub 2021 Sep 30.

Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, Netherlands.

Background: Clinicians are unable to provide individualized counseling regarding risk of progression for patients with a complete hydatidiform mole (CHM). We developed nomograms enabling early prediction of post-molar gestational trophoblastic neoplasia (GTN) and resistance to methotrexate (MTX) based on a single serum human chorion gonadotropin (hCG) measurement.

Methods: We generated two nomograms with logistic regression: to predict post-molar GTN, and MTX resistance. For patients with high probability to progress to post-molar GTN or MTX resistance, we determined hCG cut-offs at 97.5% specificity to select patients for additional- or adjustments in current treatment.

Results: The nomograms had a good to excellent ability to distinguish either between patients with uneventful hCG regression versus progression to post molar GTN, or between patients cured by MTX versus patients in whom resistance would occur. At 97.5% specificity, we identified 66% (95%CI 56-75) of the 149 patients who would progress to post-molar GTN, four weeks after initial curettage. For patients treated with MTX, we identified 55% (95%CI 23-83) of the 43 patients who would become resistant, preceding their third course at 97.5% specificity.

Conclusion: The nomograms and cut-off levels can be used to assist in counseling for patients diagnosed with CHM.
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http://dx.doi.org/10.1016/j.ygyno.2021.09.016DOI Listing
December 2021

Imaging modalities for the detection of posterior pelvic floor disorders in women with obstructed defaecation syndrome.

Cochrane Database Syst Rev 2021 09 23;9:CD011482. Epub 2021 Sep 23.

Department of Obstetrics and Gynaecology, Croydon University Hospital NHS Trust, Croydon, UK.

Background: Obstructed defaecation syndrome (ODS) is difficulty in evacuating stools, requiring straining efforts at defaecation, having the sensation of incomplete evacuation, or the need to manually assist defaecation. This is due to a physical blockage of the faecal stream during defaecation attempts, caused by rectocele, enterocele, intussusception, anismus or pelvic floor descent. Evacuation proctography (EP) is the most common imaging technique for diagnosis of posterior pelvic floor disorders. It has been regarded as the reference standard because of extensive experience, although it has been proven not to have perfect accuracy. Moreover, EP is invasive, embarrassing and uses ionising radiation. Alternative imaging techniques addressing these issues have been developed and assessed for their accuracy. Because of varying results, leading to a lack of consensus, a systematic review and meta-analysis of the literature are required.

Objectives: To determine the diagnostic test accuracy of EP, dynamic magnetic resonance imaging (MRI) and pelvic floor ultrasound for the detection of posterior pelvic floor disorders in women with ODS, using latent class analysis in the absence of a reference standard, and to assess whether MRI or ultrasound could replace EP. The secondary objective was to investigate differences in diagnostic test accuracy in relation to the use of rectal contrast, evacuation phase, patient position and cut-off values, which could influence test outcome.

Search Methods: We ran an electronic search on 18 December 2019 in the Cochrane Library, MEDLINE, Embase, SCI, CINAHL and CPCI. Reference list, Google scholar. We also searched WHO ICTRP and clinicaltrials.gov for eligible articles. Two review authors conducted title and abstract screening and full-text assessment, resolving disagreements with a third review author.

Selection Criteria: Diagnostic test accuracy and cohort studies were eligible for inclusion if they evaluated the test accuracy of EP, and MRI or pelvic floor ultrasound, or both, for the detection of posterior pelvic floor disorders in women with ODS. We excluded case-control studies. If studies partially met the inclusion criteria, we contacted the authors for additional information.

Data Collection And Analysis: Two review authors performed data extraction, including study characteristics, 'Risk-of-bias' assessment, sources of heterogeneity and test accuracy results. We excluded studies if test accuracy data could not be retrieved despite all efforts. We performed meta-analysis using Bayesian hierarchical latent class analysis. For the index test to qualify as a replacement test for EP, both sensitivity and specificity should be similar or higher than the historic reference standard (EP), and for a triage test either specificity or sensitivity should be similar or higher. We conducted heterogeneity analysis assessing the effect of different test conditions on test accuracy. We ran sensitivity analyses by excluding studies with high risk of bias, with concerns about applicability, or those published before 2010. We assessed the overall quality of evidence (QoE) according to GRADE.

Main Results: Thirty-nine studies covering 2483 participants were included into the meta-analyses. We produced pooled estimates of sensitivity and specificity for all index tests for each target condition. Findings of the sensitivity analyses were consistent with the main analysis. Sensitivity of EP for diagnosis of rectocele was 98% (credible interval (CrI)94%-99%), enterocele 91%(CrI 83%-97%), intussusception 89%(CrI 79%-96%) and pelvic floor descent 98%(CrI 93%-100%); specificity for enterocele was 96%(CrI 93%-99%), intussusception 92%(CrI 86%-97%) and anismus 97%(CrI 94%-99%), all with high QoE. Moderate to low QoE showed a sensitivity for anismus of 80%(CrI 63%-94%), and specificity for rectocele of 78%(CrI 63%-90%) and pelvic floor descent 83%(CrI 59%-96%). Specificity of MRI for diagnosis of rectocele was 90% (CrI 79%-97%), enterocele 99% (CrI 96%-100%) and intussusception 97% (CrI 88%-100%), meeting the criteria for a triage test with high QoE. MRI did not meet the criteria to replace EP. Heterogeneity analysis showed that sensitivity of MRI performed with evacuation phase was higher than without for rectocele (94%, CrI 87%-98%) versus 65%, CrI 52% to 89%, and enterocele (87%, CrI 74%-95% versus 62%, CrI 51%-88%), and sensitivity of MRI without evacuation phase was significantly lower than EP. Specificity of transperineal ultrasound (TPUS) for diagnosis of rectocele was 89% (CrI 81%-96%), enterocele 98% (CrI 95%-100%) and intussusception 96% (CrI 91%-99%); sensitivity for anismus was 92% (CrI 72%-98%), meeting the criteria for a triage test with high QoE. TPUS did not meet the criteria to replace EP. Heterogeneity analysis showed that sensitivity of TPUS performed with rectal contrast was not significantly higher than without for rectocele(92%, CrI 69%-99% versus 81%, CrI 58%-95%), enterocele (90%, CrI 71%-99% versus 67%, CrI 51%-90%) and intussusception (90%, CrI 69%-98% versus 61%, CrI 51%-86%), and was lower than EP. Specificity of endovaginal ultrasound (EVUS) for diagnosis of rectocele was 76% (CrI 54%-93%), enterocele 97% (CrI 80%-99%) and intussusception 93% (CrI 72%-99%); sensitivity for anismus was 84% (CrI 59%-96%), meeting the criteria for a triage test with very low to moderate QoE. EVUS did not meet the criteria to replace EP. Specificity of dynamic anal endosonography (DAE) for diagnosis of rectocele was 88% (CrI 62%-99%), enterocele 97% (CrI 75%-100%) and intussusception 93% (CrI 65%-99%), meeting the criteria for a triage test with very low to moderate QoE. DAE did not meet the criteria to replace EP. Echodefaecography (EDF) had a sensitivity of 89% (CrI 65%-98%) and specificity of 92% (CrI 72%-99%) for intussusception, meeting the criteria to replace EP but with very low QoE. Specificity of EDF for diagnosis of rectocele was 89% (CrI 60%-99%) and for enterocele 97% (CrI 87%-100%); sensitivity for anismus was 87% (CrI 72%-96%), meeting the criteria for a triage test with low to very low QoE.

Authors' Conclusions: In a population of women with symptoms of ODS, none of the imaging techniques met the criteria to replace EP. MRI and TPUS met the criteria of a triage test, as a positive test confirms diagnosis of rectocele, enterocele and intussusception, and a negative test rules out diagnosis of anismus. An evacuation phase increased sensitivity of MRI. Rectal contrast did not increase sensitivity of TPUS. QoE of EVUS, DAE and EDF was too low to draw conclusions. More well-designed studies are required to define their role in the diagnostic pathway of ODS.
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http://dx.doi.org/10.1002/14651858.CD011482.pub2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8459393PMC
September 2021

Practice pattern variation: treatment of pelvic organ prolapse in The Netherlands.

Int Urogynecol J 2021 Sep 6. Epub 2021 Sep 6.

Department of Obstetrics and Gynecology, Isala, Zwolle, The Netherlands.

Introduction And Hypothesis: Great variety in clinical management of pelvic organ prolapse (POP) has been described over the last years. Practice pattern variation (PPV) reflects differences in care that cannot be explained by the underlying condition. We aim to explore whether PPV in management of POP in The Netherlands has changed between 2011 and 2017.

Methods: We conducted a multicenter cohort study, using prospective routinely collected benchmark data from LOGEX, a healthcare analytics company (Amsterdam, The Netherlands). Data of patients with a diagnosis POP from 50 hospitals (16 teaching and 34 non-teaching hospitals) were collected for the years 2011 and 2017. All treatments were categorized into three groups: conservative treatment, uterus-preserving or uterus-removing surgery. Using meta-analysis, we evaluated whether the proportions of conducted treatments changed over time and estimated the between-center variation (Cochran's Q), reflecting the PPV in 2011 and 2017. This variation was analyzed using F-tests.

Results: Compared to 2011, referral for POP in 2017 decreased by 16.2% (-4505 patients), and the percentage of hysterectomies decreased by 33.6% (p < 0.0001). The PPV of POP surgery decreased significantly by 47.2% (p = 0.0137) and of hysterectomies by 41.5% (p = 0.0316).

Conclusions: We found a decline in PPV for POP surgery between 2011 and 2017. Furthermore, the number of surgical interventions decreased, which was mostly due to a decline of hysterectomies. This indicates a shift toward more conservative therapy and uterus preservation. A further reduction of PPV would be beneficial for the quality of health care.
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http://dx.doi.org/10.1007/s00192-021-04968-8DOI Listing
September 2021

Evaluation of a patient decision aid for BRCA1/2 pathogenic variant carriers choosing an ovarian cancer prevention strategy.

Gynecol Oncol 2021 11 27;163(2):371-377. Epub 2021 Aug 27.

Radboud University Medical Center, Scientific Institute for Quality of Healthcare, PO Box 9101, 6500, HB, Nijmegen, the Netherlands.

Objective: Risk-reducing surgery is advised to BRCA1/2 pathogenic variant (PV) carriers around the age of 40 years to reduce ovarian cancer risk. In the TUBA-study, a multicenter preference study (NCT02321228), BRCA1/2-PV carriers are offered a choice: the standard strategy of risk-reducing salpingo-oophorectomy or the novel strategy of risk-reducing salpingectomy with delayed oophorectomy. We evaluated feasibility and effectiveness of a patient decision aid for this choice.

Methods: Premenopausal BRCA1/2-PV carriers were counselled for risk-reducing surgical options in the TUBA-study; the first cohort was counselled without and the second cohort with decision aid. Evaluation was performed using digital questionnaires for participating women and their healthcare professionals. Outcome measures included actual choice, feasibility (usage and experiences) and effectiveness (knowledge, cancer worry, decisional conflict, decisional regret and self-estimated influence on decision).

Results: 283 women were counselled without and 282 women with decision aid. The novel strategy was chosen less frequently in women without compared with women with decision aid (67% vs 78%, p = 0.004). The decision aid was graded with an 8 out of 10 by both women and professionals, and 78% of the women would recommend this decision aid to others. Users of the decision aid reported increased knowledge about the options and increased insight in personal values. Knowledge on cancer risk, decisional conflict, decisional regret and cancer worry were similar in both cohorts.

Conclusions: The use of the patient decision aid for risk-reducing surgery is feasible, effective and highly appreciated among BRCA1/2-PV carriers facing the decision between salpingo-oophorectomy or salpingectomy with delayed oophorectomy.
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http://dx.doi.org/10.1016/j.ygyno.2021.08.019DOI Listing
November 2021

Improving preoperative diagnosis in endometrial cancer using systematic morphological assessment and a small immunohistochemical panel.

Hum Pathol 2021 11 19;117:68-78. Epub 2021 Aug 19.

Dept. Pathology, Radboud University Medical Center, 6500 HB, Nijmegen, the Netherlands.

Preoperative histopathological classification determines the primary surgical approach in endometrial carcinoma (EC) patients but has only moderate agreement between preoperative and postoperative diagnosis. The aim of the PIpelle Prospective ENDOmetrial carcinoma (PIPENDO) study is to determine whether histopathological assessment and a small panel of diagnostic biomarkers decreases discrepancies between preoperative and postoperative diagnosis in EC. Preoperative endometrial tissue of 378 included patients with EC was stained with 15 different antibodies. Clinically relevant discrepancies in grade or histological subtype between original preoperative and reviewed postoperative diagnosis were observed in 75 (20%) patients. Highest clinically relevant discrepancy was found in grade 2 ECs (20%), compared to 5% and 14% in respectively grade 1 and 3 endometrioid endometrial carcinomas (EECs). A practical two-biomarker panel with PR and p53 improved diagnostic accuracy (AUC = 0.92; 95%CI = 0.88-0.95) compared to solely morphological evaluation (AUC = 0.86). In preoperative high-grade EC, the diagnostic accuracy of histological subtype was improved by a three-immunohistochemical biomarker panel (PR, IMP3, and L1CAM) (AUC = 0.93; 95%CI = 0.88-0.98) compared to solely morphological evaluation (AUC = 0.81). In conclusion to improve correct preoperative diagnosis in EC, we recommend use of a panel of at least two easily accessible immunohistochemical biomarkers (PR and p53), only in grade 2 ECs. Overall, this will reduce clinically relevant discrepancies in tumor grade and subtype with postoperative diagnosis with 6% (from 20% to 14%). Addition of PR, IMP3, and L1CAM for histological subtyping in high-grade EECs resulted in a further decrease in discrepancies with 8% (from 20% to 12%).
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http://dx.doi.org/10.1016/j.humpath.2021.08.006DOI Listing
November 2021

A tutorial on individualized treatment effect prediction from randomized trials with a binary endpoint.

Stat Med 2021 11 16;40(26):5961-5981. Epub 2021 Aug 16.

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

Randomized trials typically estimate average relative treatment effects, but decisions on the benefit of a treatment are possibly better informed by more individualized predictions of the absolute treatment effect. In case of a binary outcome, these predictions of absolute individualized treatment effect require knowledge of the individual's risk without treatment and incorporation of a possibly differential treatment effect (ie, varying with patient characteristics). In this article, we lay out the causal structure of individualized treatment effect in terms of potential outcomes and describe the required assumptions that underlie a causal interpretation of its prediction. Subsequently, we describe regression models and model estimation techniques that can be used to move from average to more individualized treatment effect predictions. We focus mainly on logistic regression-based methods that are both well-known and naturally provide the required probabilistic estimates. We incorporate key components from both causal inference and prediction research to arrive at individualized treatment effect predictions. While the separate components are well known, their successful amalgamation is very much an ongoing field of research. We cut the problem down to its essentials in the setting of a randomized trial, discuss the importance of a clear definition of the estimand of interest, provide insight into the required assumptions, and give guidance with respect to modeling and estimation options. Simulated data illustrate the potential of different modeling options across scenarios that vary both average treatment effect and treatment effect heterogeneity. Two applied examples illustrate individualized treatment effect prediction in randomized trial data.
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http://dx.doi.org/10.1002/sim.9154DOI Listing
November 2021

The Natural History of Cervical Intraepithelial Neoplasia Grades 1, 2, and 3: A Systematic Review and Meta-analysis.

J Low Genit Tract Dis 2021 Jul;25(3):221-231

Division of Gynecologic Oncology, Queen Elizabeth II Health Sciences Centre, Halifax, Nova Scotia, Canada.

Objective: The aim of the study was to obtain an updated overview of regression, persistence, and progression rates of conservatively managed cervical intraepithelial neoplasia grade 1 (CIN 1)/CIN 2/CIN 3.

Methods: Data sources were MEDLINE, Embase, and Cochrane (January 1, 1973-April 14, 2020). Two reviewers extracted data and assessed risk of bias. To estimate outcome rates, we pooled proportions of the individual study results using random-effects meta-analysis, resulting in point estimates and corresponding 95% CIs. Heterogeneity was quantified by the I2 and τ2 measures.

Results: Eighty-nine studies were included, 63 studies on CIN 1 (n = 6,080-8,767), 42 on CIN 2 (n = 2,909-3,830), and 7 on CIN 3 (n = 245-351). The overall regression, persistence, and progression to CIN 2 or worse and CIN 3 or worse rates for women with conservatively managed CIN 1 were 60% (95% CI = 55-65, I2 = 92%), 25% (95% CI = 20-30, I2 = 94%), 11% (95% CI = 8-13, I2 = 89%), and 2% (95% CI = 1-3, I2 = 82%), respectively. The overall regression, persistence, and progression rates for CIN 2 were 55% (95% CI = 50-60, I2 = 85%), 23% (95% CI = 19-28, I2 = 83%), and 19% (95% CI = 15-23, I2 = 88%), respectively. Finally, for CIN 3, these were 28% (95% CI = 17-41, I2 = 68%), 67% (95% CI = 36-91, I2 = 84%), and 2% (95% CI = 0-25, I2 = 95%), respectively. Cervical intraepithelial neoplasia grade 2 regression was significantly higher in women 30 years or younger and high-risk human papillomavirus-negative women (66%, 95% CI = 62-70, I2 = 76%; 94%, 95% CI = 84-99, I2 = 60%). Only 2/7,180 (0.03%) and 10/3,037 (0.3%) of the CIN 1 and CIN 2 cases progressed to cervical cancer.

Conclusions: Most CIN 1/CIN 2 will regress spontaneously in less than 24 months, with the highest rates in high-risk human papillomavirus-negative and young women, whereas progression to cancer is less than 0.5%. Conservative management should be considered, especially in fertile women and with expected high compliance. Given the heterogeneity in regression rates of high-grade histology, this should be classified as CIN 2 or CIN 3 to guide management.
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http://dx.doi.org/10.1097/LGT.0000000000000604DOI Listing
July 2021

Association of Salpingectomy With Delayed Oophorectomy Versus Salpingo-oophorectomy With Quality of Life in BRCA1/2 Pathogenic Variant Carriers: A Nonrandomized Controlled Trial.

JAMA Oncol 2021 Aug;7(8):1203-1212

Radboud Institute for Health Sciences, Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, the Netherlands.

Importance: Most women with a BRCA1/2 pathogenic variant undergo premature menopause with potential short- and long-term morbidity due to the current method of ovarian carcinoma prevention: risk-reducing salpingo-oophorectomy (RRSO). Because the fallopian tubes play a key role in ovarian cancer pathogenesis, salpingectomy with delayed oophorectomy may be a novel risk-reducing strategy with benefits of delaying menopause.

Objective: To compare menopause-related quality of life after risk-reducing salpingectomy (RRS) with delayed oophorectomy with RRSO in carriers of the BRCA1/2 pathogenic variant.

Design, Setting, And Participants: A multicenter nonrandomized controlled preference trial (TUBA study), with patient recruitment between January 16, 2015, and November 7, 2019, and follow-up at 3 and 12 months after surgery was conducted in all Dutch university hospitals and a few large general hospitals. In the Netherlands, RRSO is predominantly performed in these hospitals. Patients at the clinical genetics or gynecology department between the ages of 25 and 40 years (BRCA1) or 25 to 45 years (BRCA2) who were premenopausal, had completed childbearing, and were undergoing no current treatment for cancer were eligible.

Interventions: Risk-reducing salpingo-oophorectomy at currently recommended age or RRS after completed childbearing with delayed oophorectomy. After RRSO was performed, hormone replacement therapy was recommended for women without contraindications.

Main Outcomes And Measures: Menopause-related quality of life as assessed by the Greene Climacteric Scale, with a higher scale sum (range, 0-63) representing more climacteric symptoms. Secondary outcomes were health-related quality of life, sexual functioning and distress, cancer worry, decisional regret, and surgical outcomes.

Results: A total of 577 women (mean [SD] age, 37.2 [3.5] years) were enrolled: 297 (51.5%) were pathogenic BRCA1 variant carriers and 280 (48.5%) were BRCA2 pathogenic variant carriers. At the time of analysis, 394 patients had undergone RRS and 154 had undergone RRSO. Without hormone replacement therapy, the adjusted mean increase from the baseline score on the Greene Climacteric Scale was 6.7 (95% CI, 5.0-8.4; P < .001) points higher during 1 year after RRSO than after RRS. After RRSO with hormone replacement therapy, the difference was 3.6 points (95% CI, 2.3-4.8; P < .001) compared with RRS.

Conclusions And Relevance: Results of this nonrandomized controlled trial suggest that patients have better menopause-related quality of life after RRS than after RRSO, regardless of hormone replacement therapy. An international follow-up study is currently evaluating the oncologic safety of this therapy.

Trial Registration: ClinicalTrials.gov Identifier: NCT02321228.
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http://dx.doi.org/10.1001/jamaoncol.2021.1590DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8176392PMC
August 2021

Latent Class Analysis to Predict Outcomes of Early High-Intensity Physical Therapy After Total Knee Arthroplasty, Based on Longitudinal Trajectories of Walking Speed.

J Orthop Sports Phys Ther 2021 07 10;51(7):362-371. Epub 2021 May 10.

Objective: To (1) classify patients who are recovering from total knee arthroplasty (TKA) based on walking speed during an early physical therapy program, and (2) assess whether walking-speed trajectory predicts performance on the timed up-and-go (TUG) test.

Design: Cohort study.

Methods: We included 218 patients from a 10-day physical therapy program after TKA. A latent class mixed model was used to classify patients according to their walking-speed trajectory during the program. We assessed the change in TUG test score from pre-TKA to 6 weeks and 1 year after TKA. The association between change in TUG test score and walking-speed trajectory was assessed using multivariable regression.

Results: There were 2 groups with distinct walking-speed trajectories: a high-gain group (46%) and a low-gain group (54%). There was no significant association between change in TUG test score and walking-speed trajectory after TKA and physical therapy. Function (based on TUG test performance) improved for all patients 1 year after TKA, irrespective of walking-speed trajectory (ie, high or low gain) early in postoperative physical therapy.

Conclusion: Although we distinguished different groups based on functional outcomes during physical therapy, the clinical relevance of classifying patients based on walking speed remains unclear, as it did not predict short- and long-term functional outcomes. .
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http://dx.doi.org/10.2519/jospt.2021.10299DOI Listing
July 2021

Effects of multimodal balance training supported by rhythmical auditory stimuli in people with advanced stages of Parkinson's disease: a pilot randomized clinical trial.

J Neurol Sci 2020 Nov 11;418:117086. Epub 2020 Aug 11.

Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, Centre of Expertise for Parkinson & Movement Disorders, Nijmegen, the Netherlands.

Non-pharmacological interventions such as physiotherapy are recognized as important elements in the overall clinical management of motor impairments in PD, but evidence of physiotherapy in advanced disease stages is sparse. A recent trial found positive effects of multimodal balance training in people with mild to moderate PD, with greater and more sustained effects when rhythmical auditory stimuli were added. It is unclear whether such multimodal balance training is also effective in people with advanced PD (Hoehn & Yahr stage 4).

Methods: We performed a pilot prospective single-blind, randomized clinical trial to study the effectiveness of multimodal training with and without rhythmical auditory stimuli. We screened 76 people with Parkinson's disease and Hoehn & Yahr stage 4 by telephone; 35 patients were assigned randomly into two groups: (1) multimodal balance training with rhythmical auditory stimuli (RAS-supported intervention, n = 17) and (2) multimodal balance training without rhythmical auditory cues (n = 18). Training was performed for 5 weeks, two times/week. Primary outcome was the Mini-BESTest (MBEST) score immediately after the training period. Assessments were performed by the same two blinded assessors at baseline, immediately post intervention, and after one and 6-months follow-up.

Results: Immediately post-intervention, both intervention groups improved significantly on Mini-Best scores, without differences between both intervention modalities. In both groups, results were retained at one-month follow-up. At 6-months follow-up, the effects were retained only in the RAS-supported intervention group. For both intervention groups, no improvements were found on secondary outcome measures for gait.

Conclusion: Both RAS-supported multimodal balance training and regular multimodal balance training improve balance in PD patients in advanced disease stages. Effects appear to sustain longer in the RAS-supported training group.
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http://dx.doi.org/10.1016/j.jns.2020.117086DOI Listing
November 2020

Reduced morbidity by using LigaSure compared to conventional inguinofemoral lymphadenectomy in vulvar cancer patients: A randomized controlled trial.

Surg Oncol 2020 Dec 13;35:149-155. Epub 2020 Aug 13.

Department of Obstetrics and Gynaecology, Radboud Institute for Health Sciences, Radboud university Medical Center, Nijmegen, the Netherlands.

Background: Inguinofemoral lymphadenectomy (IFL) is part of the surgical treatment of different malignancies of the genital tract and/or the lower limb including vulvar carcinoma, penile carcinoma and melanoma. IFL is associated with morbidity in up to 85% of the patients. The aims of this MAMBO-IC study (Morbidity And Measurement of the Body) are to study the feasibility of using LigaSure for IFL and to assess the differences in the incidence of short-term complications using LigaSure versus conventional IFL randomized within each individual patient.

Methods: In this multicenter randomized controlled trial (RCT), women diagnosed with squamous cell carcinoma of the vulva with an indication for bilateral IFL were included. It was randomly assigned for which groin the LigaSure was used; the other groin was treated with conventional IFL (sharp/diathermia). We estimated the incidence of ≥1 complication(s) per groin using logistic regression and compared this between the two surgical methods, adjusting for possible confounders.

Results: We included 40 groins of 20 patients. The estimated incidence of ≥1 complication(s) was 29% after LigaSure versus 70% after conventional IFL (risk difference 41% (95% CI 19-62), p < 0.001). Patients' reported restriction of daily living activities and maximum pain score were equal for both treatment methods. There were no differences in the surgeon reported workload scores.

Conclusions: This RCT shows that LigaSure for IFL is feasible and associated with significantly less short-term surgical complications compared to conventional IFL. Further studies with a larger sample size are needed to validate our findings. ISRCTN15057626.
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http://dx.doi.org/10.1016/j.suronc.2020.08.011DOI Listing
December 2020

Multimodal Balance Training Supported by Rhythmic Auditory Stimuli in Parkinson Disease: Effects in Freezers and Nonfreezers.

Phys Ther 2020 10;100(11):2023-2034

Donders Institute for Brain, Cognition and Behaviour, Department of Neurology, and Center of Expertise for Parkinson & Movement Disorders, Radboud University Medical Center.

Objective: To fulfill the potential of nonpharmacological interventions for people with Parkinson disease (PD), individually tailored treatment is needed. Multimodal balance training supported by rhythmic auditory stimuli (RAS) can improve balance and gait in people with PD. The purpose of this study was to determine whether both freezers and nonfreezers benefit.

Methods: A secondary analysis was conducted on a large randomized controlled trial that included 154 patients with PD (Hoehn & Yahr Stages 1-3 while ON-medication) who were assigned randomly to 3 groups: (1) multimodal balance training with RAS delivered by a metronome (RAS-supported multimodal balance training); (2) regular multimodal balance training without rhythmic auditory cues; and (3) a control intervention (involving an educational program). Training was performed for 5 weeks, twice per week. The primary outcome was the Mini-BESTest score directly after the training period. Assessments were performed by a single, masked assessor at baseline, directly postintervention, and after 1-month and 6-month follow-up. Outcomes were analyzed in 1 analysis, and the results were presented separately for freezers and nonfreezers with a linear mixed model, adjusted for baseline Mini-BESTest scores, Unified Parkinson's Disease Rating Scale scores, and levodopa equivalent dose.

Results: In both freezers and nonfreezers, both RAS-supported multimodal training and regular training significantly improved the Mini-BESTest scores compared with baseline scores and with the control group scores. The improvement was larger for RAS-supported training compared with regular training, for both freezers and nonfreezers. Only the RAS-supported training group retained the improvements compared with baseline measurements at 6-month follow-up, and this was true for both freezers and nonfreezers.

Conclusions: RAS-supported multimodal training is effective in improving balance performance in both freezers and nonfreezers.

Impact: Until this study, it was unknown whether both freezers and nonfreezers could benefit from multimodal balance training. With this information, clinicians who work with people with PD will be better able to apply personalized gait rehabilitation.

Lay Summary: Adding rhythmic auditory stimuli (RAS) to balance training is beneficial for both freezers and nonfreezers, at least in persons with mild to moderate disease stages. This RAS-supported multimodal training has good potential for a wider clinical implementation with good long-term effects.
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http://dx.doi.org/10.1093/ptj/pzaa146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7596891PMC
October 2020

The Impact of the Extent of Surgery on the Long-Term Outcomes of Patients with Low-Risk Differentiated Non-Medullary Thyroid Cancer: A Systematic Meta-Analysis.

J Clin Med 2020 Jul 21;9(7). Epub 2020 Jul 21.

Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands.

Recently, the management of patients with low-risk differentiated non-medullary thyroid cancer (DTC), including papillary and follicular thyroid carcinoma subtypes, has been critically appraised, questioning whether these patients might be overtreated without a clear clinical benefit. The American Thyroid Association (ATA) guideline suggests that thyroid lobectomy (TL) could be a safe alternative for total thyroidectomy (TT) in patients with DTC up to 4 cm limited to the thyroid, without metastases. We conducted a meta-analysis to assess the clinical outcomes in patients with low-risk DTC based on the extent of surgery. The risk ratio (RR) of recurrence rate, overall survival (OS), disease-free survival (DFS) and disease specific survival (DSS) were estimated. In total 16 studies with 175,430 patients met the inclusion criteria. Overall, low recurrence rates were observed for both TL and TT groups (7 vs. 7%, RR 1.10, 95% CI 0.61-1.96, = 72%), and no statistically significant differences for OS (TL 94.1 vs. TT 94.4%, RR 0.99, CI 0.99-1.00, = 53%), DFS (TL 87 vs. TT 91%, RR 0.96, CI 0.89-1.03, = 85%), and DSS (TL 97.2 vs. TT 95.4%, RR 1.01, CI 1.00-1.01, = 74%). The high degree of heterogeneity of the studies is a notable limitation. Conservative management and appropriate follow-up instead of bilateral surgery would be justifiable in selected patients. These findings highlight the importance of shared-decision making in the management of patients with small, low-risk DTC.
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http://dx.doi.org/10.3390/jcm9072316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408649PMC
July 2020

Impact of a nutritional supplement (Impryl) on male fertility: study protocol of a multicentre, randomised, double-blind, placebo-controlled clinical trial (SUppleMent Male fERtility, SUMMER trial).

BMJ Open 2020 07 2;10(7):e035069. Epub 2020 Jul 2.

Obstetrics and Gynaecology, Radboudumc, Nijmegen, The Netherlands.

Introduction: Infertility is a worldwide problem and about 10%-15% of all couples will be affected by the inability to have children. In approximately 50% of infertile couples, a male factor is involved. Most of the male infertile cases are characterised as 'idiopathic', except for a small percentage of cases which are causative by a genetic aetiology. In the past decade, the role of oxidative stress related to sperm quality has been researched thoroughly and estimated to be the problem in 25%-87% of male infertility cases. Impryl is a nutritional supplement which works on the metabolic system and the regulation of oxidative stress by activating the 1-carbon cycle and therefore recycling of homocysteine. We hypothesise that the nutritional supplement Impryl in men of infertile couples might improve the ongoing pregnancy rate.

Methods And Analysis: We designed a multicentre, randomised, double-blind, placebo-controlled clinical trial. We aimed to include 1200 male adults aged 18-50 years, part of a couple that is diagnosed with infertility. The couple will either start or has already been started with fertility treatment, that is, expectative management (duration of 6 months), intrauterine insemination (IUI) with or without mild ovarian stimulation or ovulation induction, either in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatment. Male participants will be randomised in either the Impryl or the placebo group, with identical appearance of the tablets to be distributed (doses: one tablet each day), for a total duration of maximal 6 months. Patients can start directly with fertility treatment and/or natural conception. The primary outcome is the number of ongoing pregnancies confirmed by ultrasound at ≥10 to 12 weeks, and conceived in the time window between randomisation up to and including month 6 of intervention use. Secondary outcomes are change in semen parameters between baseline and after 3 months of intervention in the IUI/IVF/ICSI group, based on (prewash) total motile sperm count. Furthermore the number of pregnancies conceived in the optimal intervention time window (after full spermatogenesis of 72 days), overall number of pregnancies, time to pregnancy, embryo fertilisation rate in IVF/ICSI, embryo-utilisation rate in IVF/ICSI, number of miscarriages, live birth rate and adverse events are documented within the study period of 15 months.

Ethics And Dissemination: The protocol is approved by the local medical ethical review committee at the Radboud University Medical Centre and by the national Central Committee on Research Involving Human Subjects. Findings will be shared with the academic and medical community, funding and patient organisations in order to contribute to optimisation of medical care and quality of life for patients with infertility.

Trial Registration Numbers: NCT03337360 and NTR6551.
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http://dx.doi.org/10.1136/bmjopen-2019-035069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333867PMC
July 2020

The risk of cervical cancer after cervical intraepithelial neoplasia grade 3: A population-based cohort study with 80,442 women.

Gynecol Oncol 2020 04 20;157(1):195-201. Epub 2020 Jan 20.

Department of Obstetrics and Gynecology, Catharina Hospital, PO Box 1350, 5602ZA Eindhoven, the Netherlands. Electronic address:

Objective: To estimate the risk of cervical cancer in women with a history of cervical intraepithelial neoplasia (CIN) grade 3 and to review the compliance with post-treatment follow-up.

Methods: A population-based retrospective cohort study including 80,442 women with a median follow-up of 15.8 years, and 1,278,297 person years. Women with CIN3 between 1990 and 2010 were identified from the Dutch Pathology Registry (PALGA) and linked to the general female population from the Netherlands Cancer Registry. Cases of recurrent CIN3 and cervical cancer, defined as occurrence minimally two years post-treatment, were identified until 2016. Standardized incidence ratios (SIRs) were calculated for the risk of cervical cancer.

Results: 1554 women (1.9%) developed recurrent CIN3 and 397 women (0.5%) cervical cancer. Women with CIN3 were associated with a twofold increased risk of cervical cancer (SIR 2.29; 95%CI 2.07-2.52) compared with the general female population. Women aged ≥50 years during CIN3 diagnosis had a sevenfold and women with recurrent CIN3 a ninefold increased risk of developing cervical cancer. The increased risk up to 20 years of follow-up seems to be mostly attributable to ageing. 37.0% of women who developed cervical cancer after CIN3 did not complete the advised post-treatment follow-up.

Conclusions: Women with CIN3 have a long-lasting twofold increased risk of developing cervical cancer, even when they complete the post-treatment follow-up and adhere to the regular screening program. This risk increases with CIN3 diagnosis at older age, further ageing during follow-up and in women with recurrent CIN3. Studies on optimizing follow-up strategies are warranted.
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http://dx.doi.org/10.1016/j.ygyno.2020.01.023DOI Listing
April 2020

Multimodal Balance Training Supported by Rhythmical Auditory Stimuli in Parkinson's Disease: A Randomized Clinical Trial.

J Parkinsons Dis 2020 ;10(1):333-346

Department of Neurology, Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, Centre of Expertise for Parkinson & Movement Disorders, Nijmegen, The Netherlands.

Background: Balance impairment in Parkinson's disease (PD) improves only partially with dopaminergic medication. Therefore, non-pharmacological interventions such as physiotherapy are important elements in clinical management. External cues are often applied to improve gait, but their effects on balance control are unclear.

Objective/methods: We performed a prospective, single-blind, randomized clinical trial to study the effectiveness of balance training with and without rhythmical auditory cues. We screened 201 volunteers by telephone; 154 were assigned randomly into three groups: (1) multimodal balance training supported by rhythmical auditory stimuli (n = 56) (RAS-supported multimodal balance training); (2) regular multimodal balance training without rhythmical auditory stimuli (n = 50); and (3) control intervention involving a general education program (n = 48). Training was performed for 5 weeks, two times/week. Linear mixed models were used for all outcomes. Primary outcome was the Mini-BESTest (MBEST) score immediately after the training period. Assessments were performed by a single, blinded assessor at baseline, immediately post intervention, and after one and 6-months follow-up.

Results: Immediately post intervention, RAS-supported multimodal balance training was more effective than regular multimodal balance training on MBEST (difference 3.5 (95% Confidence Interval (CI) 2.2; 4.8)), p < 0.001). Patients allocated to both active interventions improved compared to controls (MBEST estimated mean difference versus controls 6.6 (CI 5.2; 8.0), p < 0.001 for RAS-supported multimodal balance training; and 3.0 (CI 2.7; 5.3), p < 0.001 for regular multimodal balance training). Improvements were retained at one-month follow-up for both active interventions, but only the RAS-supported multimodal balance training group maintained its improvement at 6 months.

Conclusion: Both RAS-supported multimodal balance training and regular multimodal balance training improve balance, but RAS-supported multimodal balance training-adding rhythmical auditory cues to regular multimodal balance training-has greater and more sustained effects.
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http://dx.doi.org/10.3233/JPD-191752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7029328PMC
April 2021

The relative risk of noncervical high-risk human papillomavirus-related (pre)malignancies after recurrent cervical intraepithelial neoplasia grade 3: A population-based study.

Int J Cancer 2020 08 28;147(3):897-900. Epub 2019 Dec 28.

Department of Pathology, Radboud university medical center, Nijmegen, The Netherlands.

Women with cervical intraepithelial neoplasia grade 3 (CIN3) have a long-lasting increased risk for noncervical high-risk human papillomavirus (hrHPV)-related (pre)malignancies. The aim of our study was to estimate this risk in women with recurrent CIN3 compared to women without a history of CIN3 and women with a single episode of CIN3. Women with a CIN3 diagnosis between 1990 and 2010 were obtained from the Dutch Pathology Registry (PALGA) and matched with a control group of women without CIN3. Analysis has been conducted in a subset of women with recurrent CIN3, defined as reoccurrence minimally 2 years post-treatment. Cases of noncervical hrHPV-related (pre)malignancies of the anus, vulva, vagina and oropharynx were identified until 2015 and incidence rate ratios (IRRs) were estimated. Then, 1,797 women with recurrent CIN3 were included with a median age of 34 years (range 18-76) and 31,594 person-years of follow-up. Women with recurrent CIN3 had an increased risk of developing noncervical hrHPV-related (pre)malignancies compared to women without CIN3 with an IRR of 25.96 (95%CI 6.32-106.58). The IRR was 2.48 (95% CI 1.87-3.30) compared to women with a single episode of CIN3. Studies on posttreatment follow-up and prophylactic hrHPV vaccination are warranted.
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http://dx.doi.org/10.1002/ijc.32834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318313PMC
August 2020

A tutorial on dynamic risk prediction of a binary outcome based on a longitudinal biomarker.

Biom J 2020 03 28;62(2):398-413. Epub 2019 Nov 28.

Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.

Dynamic risk predictions based on all available information are useful in timely identification of high-risk patients. However, in contrast with time to event outcomes, there is still a lack of studies that clearly demonstrate how to obtain and update predictions for a future binary outcome using a repeatedly measured biomarker. The aim of this study is to give an illustrative overview of four approaches to obtain such predictions: likelihood based two-stage method (2SMLE), likelihood based joint model (JMMLE), Bayesian two-stage method (2SB), and Bayesian joint model (JMB). We applied the approaches to provide weekly updated predictions of post-molar gestational trophoblastic neoplasia (GTN) based on age and repeated measurements of human chorionic gonadotropin (hCG). Discrimination and calibration measures were used to compare the accuracy of the weekly predictions. Internal validation of the models was conducted using bootstrapping. The four approaches resulted in the same predictive and discriminative performance in predicting GTN. A simulation study showed that the joint models outperform the two-stage methods when we increase the within- and the between-patients variability of the biomarker. The applicability of these models to produce dynamic predictions has been illustrated through a comprehensive explanation and accompanying syntax (R and SAS ).
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http://dx.doi.org/10.1002/bimj.201900044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079044PMC
March 2020

Oral contraceptive and intrauterine device use and the risk of cervical intraepithelial neoplasia grade III or worse: a population-based study.

Eur J Cancer 2020 01 21;124:102-109. Epub 2019 Nov 21.

Department of Pathology, Radboud university medical center, PO Box 9101, 6500HB, Nijmegen, the Netherlands; PALGA, Randhoeve 225a, 3995 GA, Houten, the Netherlands. Electronic address:

Objective: Hormonal contraceptive use has been associated with the development of cervical cancer, although inconsistent results are reported on the association with intrauterine device (IUD) use. The aim of this study was to evaluate the association between the type of contraceptive use and the development of cervical intraepithelial neoplasia grade III or worse (CIN3+).

Methods: A retrospective population-based cohort study including women aged 29-44 years attending the cervical cancer screening program with normal cytology between 2005 and 2009 identified from the Dutch Pathology Registry. Subgroups with at least 5 years registered use of an oral contraceptive (OC) or IUD were compared with non-users. Risk ratios of CIN3+ were estimated per contraceptive type.

Results: 702,037 women were included with a median follow-up of 9.7 years, of which 6705 (0.96%) and 559 (0.08%) women developed CIN3 and cervical cancer, respectively. IUD use was associated with an increased risk of developing CIN3+ (risk ratio (RR) 1.51, 95% confidence interval (CI) 1.32-1.74), and OC use was associated with an increased risk of developing CIN3+ (RR 2.77, 95%CI 2.65-3.00) and cervical cancer (RR 2.06, 95%CI 1.52-2.79). The risk of developing CIN3+ and cervical cancer was higher for OC users compared with IUD users (RR 1.83, 95%CI 1.60-2.09 and RR 1.70, 95%CI 1.00-2.90, respectively).

Conclusions: Both OC use and IUD use were associated with an increased risk of developing CIN3+. However, for women with a contraceptive wish, an IUD seems safer than an OC as the risk of developing CIN3+ and cervical cancer was higher for OC users.
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http://dx.doi.org/10.1016/j.ejca.2019.10.009DOI Listing
January 2020

Sacrospinous hysteropexy versus vaginal hysterectomy with uterosacral ligament suspension in women with uterine prolapse stage 2 or higher: observational follow-up of a multicentre randomised trial.

BMJ 2019 Sep 10;366:l5149. Epub 2019 Sep 10.

Department of Obstetrics and Gynaecology, Isala Clinics, PO Box 10400, 8000 GK Zwolle, Netherlands.

Objective: To evaluate the effectiveness and success of uterus preserving sacrospinous hysteropexy as an alternative to vaginal hysterectomy with uterosacral ligament suspension in the surgical treatment of uterine prolapse five years after surgery.

Design: Observational follow-up of SAVE U (sacrospinous fixation versus vaginal hysterectomy in treatment of uterine prolapse ≥2) randomised controlled trial.

Setting: Four non-university teaching hospitals, the Netherlands.

Participants: 204 of 208 healthy women in the initial trial (2009-12) with uterine prolapse stage 2 or higher requiring surgery and no history of pelvic floor surgery who had been randomised to sacrospinous hysteropexy or vaginal hysterectomy with uterosacral ligament suspension. The women were followed annually for five years after surgery. This extended trial reports the results at five years.

Main Outcome Measures: Prespecified primary outcome evaluated at five year follow-up was recurrent prolapse of the uterus or vaginal vault (apical compartment) stage 2 or higher evaluated by pelvic organ prolapse quantification system in combination with bothersome bulge symptoms or repeat surgery for recurrent apical prolapse. Secondary outcomes were overall anatomical failure (recurrent prolapse stage 2 or higher in apical, anterior, or posterior compartment), composite outcome of success (defined as no prolapse beyond the hymen, no bothersome bulge symptoms, and no repeat surgery or pessary use for recurrent prolapse), functional outcome, quality of life, repeat surgery, and sexual functioning.

Results: At five years, surgical failure of the apical compartment with bothersome bulge symptoms or repeat surgery occurred in one woman (1%) after sacrospinous hysteropexy compared with eight women (7.8%) after vaginal hysterectomy with uterosacral ligament suspension (difference-6.7%, 95% confidence interval -12.8% to-0.7%). A statistically significant difference was found in composite outcome of success between sacrospinous hysteropexy and vaginal hysterectomy (89/102 (87%) 77/102 (76%). The other secondary outcomes did not differ. Time-to-event analysis at five years showed no differences between the interventions.

Conclusions: At five year follow-up significantly less anatomical recurrences of the apical compartment with bothersome bulge symptoms or repeat surgery were found after sacrospinous hysteropexy compared with vaginal hysterectomy with uterosacral ligament suspension. After hysteropexy a higher proportion of women had a composite outcome of success. Time-to-event analysis showed no differences in outcomes between the procedures.

Trial Registration: trialregister.nl NTR1866.
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http://dx.doi.org/10.1136/bmj.l5149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6734519PMC
September 2019

Statistical approaches to identify subgroups in meta-analysis of individual participant data: a simulation study.

BMC Med Res Methodol 2019 09 2;19(1):183. Epub 2019 Sep 2.

Radboud Institute for Health Sciences (RIHS), Radboud university medical center, Mailbox 133, P.O. Box 9101, Nijmegen, 6500, HB, The Netherlands.

Background: Individual participant data meta-analysis (IPD-MA) is considered the gold standard for investigating subgroup effects. Frequently used regression-based approaches to detect subgroups in IPD-MA are: meta-regression, per-subgroup meta-analysis (PS-MA), meta-analysis of interaction terms (MA-IT), naive one-stage IPD-MA (ignoring potential study-level confounding), and centred one-stage IPD-MA (accounting for potential study-level confounding). Clear guidance on the analyses is lacking and clinical researchers may use approaches with suboptimal efficiency to investigate subgroup effects in an IPD setting. Therefore, our aim is to overview and compare the aforementioned methods, and provide recommendations over which should be preferred.

Methods: We conducted a simulation study where we generated IPD of randomised trials and varied the magnitude of subgroup effect (0, 25, 50% relative reduction), between-study treatment effect heterogeneity (none, medium, large), ecological bias (none, quantitative, qualitative), sample size (50,100,200), and number of trials (5,10) for binary, continuous and time-to-event outcomes. For each scenario, we assessed the power, false positive rate (FPR) and bias of aforementioned five approaches.

Results: Naive and centred IPD-MA yielded the highest power, whilst preserving acceptable FPR around the nominal 5% in all scenarios. Centred IPD-MA showed slightly less biased estimates than naïve IPD-MA. Similar results were obtained for MA-IT, except when analysing binary outcomes (where it yielded less power and FPR < 5%). PS-MA showed similar power as MA-IT in non-heterogeneous scenarios, but power collapsed as heterogeneity increased, and decreased even more in the presence of ecological bias. PS-MA suffered from too high FPRs in non-heterogeneous settings and showed biased estimates in all scenarios. Meta-regression showed poor power (< 20%) in all scenarios and completely biased results in settings with qualitative ecological bias.

Conclusions: Our results indicate that subgroup detection in IPD-MA requires careful modelling. Naive and centred IPD-MA performed equally well, but due to less bias of the estimates in the presence of ecological bias, we recommend the latter.
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http://dx.doi.org/10.1186/s12874-019-0817-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6720416PMC
September 2019

Unraveling Hepcidin Plasma Protein Binding: Evidence from Peritoneal Equilibration Testing.

Pharmaceuticals (Basel) 2019 Aug 23;12(3). Epub 2019 Aug 23.

Department of Laboratory Medicine, Radboud University Medical Center, 6525 Nijmegen, The Netherlands.

Peptide hormone hepcidin regulates systemic iron metabolism and has been described to be partially bound to α2-macroglobulin and albumin in blood. However, the reported degree of hepcidin protein binding varies between <3% and ≈89%. Since protein-binding may influence hormone function and quantification, better insight into the degree of hepcidin protein binding is essential to fully understand the biological behavior of hepcidin and interpretation of its measurement in patients. Here, we used peritoneal dialysis to assess human hepcidin protein binding in a functional human setting for the first time. We measured freely circulating solutes in blood and peritoneal fluid of 14 patients with end-stage renal disease undergoing a peritoneal equilibration test to establish a curve describing the relation between molecular weight and peritoneal clearance. Calculated binding percentages of total cortisol and testosterone confirmed our model. The protein-bound fraction of hepcidin was calculated to be 40% (±23%). We, therefore, conclude that a substantial proportion of hepcidin is freely circulating. Although a large inter-individual variation in hepcidin clearance, besides patient-specific peritoneal transport characteristics, may have affected the accuracy of the determined binding percentage, we describe an important step towards unraveling human hepcidin plasma protein binding in vivo including the caveats that need further research.
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http://dx.doi.org/10.3390/ph12030123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6789442PMC
August 2019

Guidance from key organisations on exploring, confirming and interpreting subgroup effects of medical treatments: a scoping review.

BMJ Open 2019 08 24;9(8):e028751. Epub 2019 Aug 24.

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

Objectives: With the increasing interest in personalised medicine, the use of subgroup analyses is likely to increase. Subgroup analyses are challenging and often misused, possibly leading to false interpretations of the effect. It remains unclear to what extent key organisations warn for such pitfalls and translate current methodological research to detect these effects into research guidelines. The aim of this scoping review is to determine and evaluate the current guidance used by organisations for exploring, confirming and interpreting subgroup effects.

Design: Scoping review.

Eligibility Criteria: We identified four types of key stakeholder organisations: industry, health technology assessment organisations (HTA), academic/non-profit research organisations and regulatory bodies. After literature search and expert consultation, we identified international and national organisations of each type. For each organisation that was identified, we searched for official research guidance documents and contacted the organisation for additional guidance.

Results: Twenty-seven (45%) of the 60 organisations that we included had relevant research guidance documents. We observed large differences between organisation types: 18% (n=2) of the industry organisations, 64% (n=9) of the HTA organisations, 38% (n=8) of academic/non-profit research organisations and 57% (n=8) of regulatory bodies provided guidance documents. The majority of the documents (n=33, 63%) mentioned one or more challenges in subgroup analyses, such as false positive findings or ecological bias with variations across the organisation types. Statistical recommendations were less common (n=19, 37%) and often limited to a formal test of interaction.

Conclusions: Almost half of the organisations included in this scoping review provided guidance on subgroup effect research in their guidelines. However, there were large differences between organisations in the amount and level of detail of their guidance. Effort is required to translate and integrate research findings on subgroup analysis to practical guidelines for decision making and to reduce the differences between organisations and organisation types.
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http://dx.doi.org/10.1136/bmjopen-2018-028751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6719774PMC
August 2019

ADHD symptoms in the adult general population are associated with factors linked to ADHD in adult patients.

Eur Neuropsychopharmacol 2019 10 1;29(10):1117-1126. Epub 2019 Aug 1.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands. Electronic address:

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder in children and adults. It is characterized by inappropriate levels of inattention (IA) and/or hyperactivity and impulsivity (HI). The ADHD diagnosis is hypothesized to represent the extreme of a continuous distribution of ADHD symptoms in the general population. In this study, we investigated whether factors linked to adult ADHD as a disorder are associated with adult ADHD symptoms in the general population. Our population-based sample included 4987 adults (mean age 56.1 years; 53.8% female) recruited by the Nijmegen Biomedical Study (NBS). Participants completed the Dutch ADHD DSM-IV Rating Scale for current and childhood ADHD symptoms, the Symptom Check List-90-R (SCL-90-R) anxiety subscale, and the Eysenk Personality Questionnaire (EPQR-S). Partial Spearman correlation and Hurdle negative binomial regression analysis were used to assess how age, sex, childhood ADHD symptoms, anxiety symptoms, and personality traits (neuroticism, extraversion, and psychoticism) are associated with current IA and HI symptoms. Increasing age was associated with a lower proportion of participants reporting HI symptoms and with reduced levels of HI; IA levels remained fairly stable over the age-range, but the probability of reporting IA symptoms increased throughout middle/late adulthood. Females were more likely to report IA symptoms than males. Childhood ADHD symptoms, neuroticism, and psychoticism were positively associated with current IA and HI symptoms, while extraversion had an opposite association with these symptom domains. Anxiety symptoms affected HI symptoms in females. Our results indicate that factors associated with categorical ADHD are also correlated with ADHD symptoms in the adult population.
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http://dx.doi.org/10.1016/j.euroneuro.2019.07.136DOI Listing
October 2019

Habituation Learning Is a Widely Affected Mechanism in Drosophila Models of Intellectual Disability and Autism Spectrum Disorders.

Biol Psychiatry 2019 08 9;86(4):294-305. Epub 2019 May 9.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands. Electronic address:

Background: Although habituation is one of the most ancient and fundamental forms of learning, its regulators and its relevance for human disease are poorly understood.

Methods: We manipulated the orthologs of 286 genes implicated in intellectual disability (ID) with or without comorbid autism spectrum disorder (ASD) specifically in Drosophila neurons, and we tested these models in light-off jump habituation. We dissected neuronal substrates underlying the identified habituation deficits and integrated genotype-phenotype annotations, gene ontologies, and interaction networks to determine the clinical features and molecular processes that are associated with habituation deficits.

Results: We identified >100 genes required for habituation learning. For 93 of these genes, a role in habituation learning was previously unknown. These genes characterize ID disorders with macrocephaly and/or overgrowth and comorbid ASD. Moreover, individuals with ASD from the Simons Simplex Collection carrying damaging de novo mutations in these genes exhibit increased aberrant behaviors associated with inappropriate, stereotypic speech. At the molecular level, ID genes required for normal habituation are enriched in synaptic function and converge on Ras/mitogen-activated protein kinase (Ras/MAPK) signaling. Both increased Ras/MAPK signaling in gamma-aminobutyric acidergic (GABAergic) neurons and decreased Ras/MAPK signaling in cholinergic neurons specifically inhibit the adaptive habituation response.

Conclusions: Our work supports the relevance of habituation learning to ASD, identifies an unprecedented number of novel habituation players, supports an emerging role for inhibitory neurons in habituation, and reveals an opposing, circuit-level-based mechanism for Ras/MAPK signaling. These findings establish habituation as a possible, widely applicable functional readout and target for pharmacologic intervention in ID/ASD.
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http://dx.doi.org/10.1016/j.biopsych.2019.04.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053436PMC
August 2019

Diagnostic Accuracy of Clinical Biomarkers for Preoperative Prediction of Lymph Node Metastasis in Endometrial Carcinoma: A Systematic Review and Meta-Analysis.

Oncologist 2019 09 11;24(9):e880-e890. Epub 2019 Jun 11.

Department of Obstetrics and Gynaecology, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: In endometrial carcinoma (EC), preoperative classification is based on histopathological criteria, with only moderate diagnostic performance for the risk of lymph node metastasis (LNM). So far, existing molecular classification systems have not been evaluated for prediction of LNM. Optimized use of clinical biomarkers as recommended by international guidelines might be a first step to improve tailored treatment, awaiting future molecular biomarkers.

Aim: To determine the diagnostic accuracy of preoperative clinical biomarkers for the prediction of LNM in endometrial cancer.

Methods: A systematic review was performed according to the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. Studies identified in MEDLINE and EMBASE were selected by two independent reviewers. Included biomarkers were based on recommended guidelines (cancer antigen 125 [Ca-125], lymphadenopathy on magnetic resonance imaging, computed tomography, and F-fluorodeoxyglucose positron emission tomography/computed tomography [FDG PET-CT]) or obtained by physical examination (body mass index, cervical cytology, blood cell counts). Pooled sensitivity, specificity, area under the curve (AUC), and likelihood ratios were calculated with bivariate random-effects meta-analysis. Likelihood ratios were classified into (0.5-1.0 or 1-2.0), (0.2-0.5 or 2.0-5.0) or (0.1-0.2 or ≥ 5.0) impact.

Results: Eighty-three studies, comprising 18,205 patients, were included. Elevated Ca-125 and thrombocytosis were associated with a increase in risk of LNM; lymphadenopathy on imaging with a increase. Normal Ca-125, cytology, and no lymphadenopathy on FDG PET-CT were associated with a decrease. AUCs were above 0.75 for these biomarkers. Other biomarkers had an AUC <0.75 and incurred only impact.

Conclusion: Ca-125, thrombocytosis, and imaging had a and impact on risk of LNM and could improve preoperative risk stratification.

Implications For Practice: Routine lymphadenectomy in clinical early-stage endometrial carcinoma does not improve outcome and is associated with 15%-20% surgery-related morbidity, underlining the need for improved preoperative risk stratification. New molecular classification systems are emerging but have not yet been evaluated for the prediction of lymph node metastasis. This article provides a robust overview of diagnostic performance of all clinical biomarkers recommended by international guidelines. Based on these, at least measurement of cancer antigen 125 serum level, assessment of thrombocytosis, and imaging focused on lymphadenopathy should complement current preoperative risk stratification in order to better stratify these patients by risk.
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http://dx.doi.org/10.1634/theoncologist.2019-0117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6738307PMC
September 2019

Impact of body mass index and fat distribution on sex steroid levels in endometrial carcinoma: a retrospective study.

BMC Cancer 2019 Jun 7;19(1):547. Epub 2019 Jun 7.

Department of Obstetrics and Gynecology, Radboud University Medical Center, Geert Grooteplein 10, P.O. Box 9101, 6500, HB, Nijmegen, The Netherlands.

Background: Obesity is an important cause of multiple cancer types, amongst which endometrial cancer (EC). The relation between obesity and cancer is complicated and involves alterations in insulin metabolism, response to inflammation and alterations in estradiol metabolism. Visceral obesity is assumed to play the most important role in the first two mechanisms, but its role in estradiol metabolism is unclear. Therefore, this retrospective study explores the relationship of body mass index (BMI), visceral fat volume (VAV) and subcutaneous fat volume (SAV) and serum levels of sex steroids and lipids in patients with endometrial cancer.

Methods: Thirty-nine postmenopausal EC patients with available BMI, blood serum and Computed Tomography (CT) scans were included. Serum was analyzed for estradiol, dehydroepiandrosterone sulfate (DHEAS), androstenedione, testosterone, cholesterol, triglycerides and high (HDL), low (LDL) and non-high density (NHDL) lipoprotein. VAV and SAV were quantified on abdominal CT scan images. Findings were interpreted using pearson correlation coefficient and linear regression with commonality analysis.

Results: Serum estradiol is moderately correlated with BMI (r = 0.62) and VAV (r = 0.58) and strongly correlated with SAV (r = 0.74) (p < 0.001 for all). SAV contributes more to estradiol levels than VAV (10.3% for SAV, 1.4% for VAV, 35.9% for SAV and VAV, p = 0.01). Other sex steroids and lipids have weak and moderate correlations with VAV or SAV.

Conclusions: This study shows that serum estradiol is correlated with BMI and other fat-distribution measures in postmenopausal endometrial cancer patients. Subcutaneous fat tissue contributes more to the estradiol levels indicating that subcutaneous fat might be relevant in endometrial cancer carcinogenesis.
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http://dx.doi.org/10.1186/s12885-019-5770-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555924PMC
June 2019
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