Erasmus Medical Center Rotterdam Research Articles

Associations of bisphenol and phthalate exposure and anti-Müllerian hormone levels in women of reproductive age

In women, exposure to endocrine disrupting chemicals might accelerate the depletion of the ovarian reserve and might be associated with accelerative reproductive aging and fertility. We examined the longitudinal associations of exposure to bisphenols and phthalates with anti-Müllerian hormone concentrations. Pregnant women of 18 years or older that resided in Rotterdam between 2002 and 2006 were eligible for participation in this longitudinal prospective cohort study. We measured urinary bisphenol and phthalate concentration at three time-points in pregnancy among 1405 women, of whom 1322 women had serum Anti-Müllerian Hormone (AMH) measurements 6 and/or 9 years postpartum. We performed linear regression models to assess the association of urinary bisphenol and phthalate metabolites with AMH after 6 and 9 years, and linear mixed-effect model to assess the association with AMH over time. Models were adjusted for sociodemographic and lifestyle factors. In our multivariable linear regression models we observed associations of higher urinary pregnancy-averaged mono-isobutyl phthalate (mIBP), mono-(2-ethyl-5-oxohexyl) phthalate (mEOHP), and monobenzyl phthalate (mBzBP) with lower serum AMH after both 6 and 9 years. However, these associations did not remain after adjustment for multiple testing. No significant associations of bisphenol A with AMH were present in our study sample. In our linear mixed-effects models, higher mIBP, mono-(2-ethyl-5-hydroxyhexyl) phthalate (mEHHP), mEOHP, and mBzBP were associated with lower overall AMH levels (differences-0.07 (95% CI -0.13,-0.02),-0.09 (-0.15,-0.02),-0.08 (95% CI -0.14,-0.02), and-0.08 (-0.13,-0.03) μg/L per doubling in mIBP, mEHHP, mEOHP, and mBzBP respectively) (all False Discovery Rate adjusted p-values < 0.05). We identify decreases in indices of ovarian reserve in relationship to prenatal phthalate exposures. Studies are needed replicating our results among large multi-ethnic non-pregnant populations and assessing transgenerational effects of exposure on ovarian reserve. This study was supported by the Erasmus Medical Center and Erasmus University Rotterdam, the Netherlands Organisation for Health Research and Development, the European Research Council, the Dutch Heart Foundation, the Dutch Diabetes Foundation, the European Union's Horizon 2020 Research and Innovation Program, the National Institutes of Health, Ansh Labs Webster, and the Royal Netherlands Academy of Arts and Sciences.

P-590 Should the ovarian ultrasound markers for the diagnosis of PCOS be revised?

Abstract Study question Should the cut-off values for follicle number and ovarian volume in PCOS be revised, and should they be adjusted based on age or BMI? Summary answer The cut-off for follicle number per ovary can be maintained (age specific, not BMI adjusted), while for ovarian volume, it should be lowered or omitted. What is known already The 2023 International Guideline for PCOS concluded that the quality of evidence for recommendations regarding the ultrasound diagnosis of PCOS (FNPO ≥ 20 and/or ovarian volume (OV) ≥10 mL, in one or both ovaries) is low. It advises to regularly revise thresholds with advancing ultrasound technology and to investigate the impact of age on diagnostic accuracy. Consideration of other biological factors such as BMI is also warranted. Study design, size, duration Retrospective cross-sectional study, including data from 2001-2023, obtained through standardized endocrinological screening at the Department of Reproductive Endocrinology in the Erasmus Medical Center (Rotterdam, The Netherlands). Women diagnosed with PCOS during the screening were eligible for inclusion in the PCOS group. Women who underwent the same screening, had regular menstrual cycles, exhibited normal hormonal values, and showed no endocrinological pathology were eligible for inclusion as controls. Participants/materials, setting, methods A total of 2492 women (15-50 years) with PCOS and 152 controls were included. PCOS was diagnosed according to the 2003 Rotterdam criteria and the 2018 International Guideline. Exclusion criteria included: age &amp;lt; 15 or &amp;gt; 50 years, presence of any cysts (&amp;gt;10 mm) in one/both ovaries, use of oral contraceptives, and missing ultrasound data. The ovarian ultrasound markers were stratified by age in 5-year intervals. Receiver Operating Characteristic (ROC) analyses were performed for optimal cut-offs. Main results and the role of chance In our cohort, most women with PCOS up to age 35 exhibit a TFC ≥ 20, followed by a decline in FNPO above the age of 35. In a subgroup of women aged 35-40 (n = 24 PCOS, n = 24 controls, matched by age, assessed with ultrasound &amp;gt; 8 MHz), we found optimal cut-offs of 14.5 follicles (Left FNPO) and 14 follicles (Right FNPO), with AUC values of 0.94 and 0.93. Median OV in every age group was below the 10 mL cut-off. In women aged 20-35 (n = 75 PCOS, 75 controls, ultrasound &amp;gt; 8 MHz), optimal cut-offs were 6.5 mL (Left OV) and 7.4 mL (Right OV), with AUC values of 0.70 and 0.78. For 35-40 years, cut-offs were 8.0 mL (Left OV) and 7.2 mL (Right OV), including 24 women PCOS and 24 age-matched controls, with AUC values of 0.68 and 0.62. In our cohort 19/2413 women with PCOS (0.8%) would not have received the diagnosis PCOS if OV was not considered as a marker for PCOM. No clinically significant correlation between BMI and FNPO or OV was observed. Limitations, reasons for caution The optimal cut-off values should be interpreted with caution due to the small sample sizes in the ROC analyses. The control group includes women with isolated PCOM. There is an ongoing debate about whether they should be excluded in such analyses. Wider implications of the findings We suggest lowering or omitting the OV cut-off for PCOM detection and establishing age-specific FNPO cut-offs. Future research on ovarian markers in PCOS, should prioritize women with isolated ovulatory dysfunction or hyperandrogenism, aligning with the 2023 International PCOS Guideline recommendation to exclusively investigate PCOM in this subgroup. Trial registration number not applicable

Postoperative Delirium After Intracranial Surgery: A Retrospective Cohort Study.

The clinical relevance of postoperative delirium (POD) in neurosurgery remains unclear and should be investigated because these patients are vulnerable. Hence, we investigated the impact of POD, by means of incidence and health outcomes, and identified independent risk factors. Adult patients undergoing an intracranial surgical procedure in the Erasmus Medical Center Rotterdam between June 2017 and September 2020 were retrospectively included. POD incidence, defined by a Delirium Observation Screening Scale (DOSS) ≥3 or antipsychotic treatment for delirium within 5 days after surgery, was calculated. Logistic regression analysis on the full data set was conducted for the multivariable risk factor and health outcome analyses. After including 2901 intracranial surgical procedures, POD was present in 19.4% with a mean onset in days of 2.62 (standard deviation, 1.22) and associated with more intensive care unit admissions and more discharge toward residential care. Onset of POD was not associated with increased length of hospitalization or mortality. We identified several independent nonmodifiable risk factors such as age, preexisting memory problems, emergency operations, craniotomy compared with burr-hole surgery, and severe blood loss. Moreover, we identified modifiable risk factors such as low preoperative potassium and opioid and dexamethasone administration. Our POD incidence rates and correlation with more intensive care unit admission and discharge toward residential care suggest a significant impact of POD on neurosurgical patients. We identified several modifiable and nonmodifiable risk factors, which shed light on the pathophysiologic mechanisms of POD in this cohort and could be targeted for future intervention studies.

Dissecting the In Vitro Efficacy of Octreotide and Cabergoline in GH- and GH/PRL-Secreting Pituitary Tumors.

Cabergoline (CAB) is an off-label medical therapy for acromegaly, overshadowed by first-generation somatostatin receptor ligands, eg, octreotide (OCT). This was a head-to-head comparison between OCT and CAB in inhibiting growth hormone (GH) secretion in primary cultures of GH- and GH/prolactin (PRL)-secreting tumors; we also investigated the role of somatostatin (SST) and dopamine type 2 (D2R) receptor expression. We evaluated the antisecretory effect of OCT and CAB, together with receptor mRNA expression, in 23 tumor cultures obtained from acromegaly patients referred to the Erasmus Medical Center (Rotterdam, The Netherlands). GH concentrations in cell culture media were determined after 72-hour OCT and CAB treatment (10 nM). OCT showed a slightly higher efficacy compared with CAB (GH decrease -39.5% vs -32.5%, P = 0.079). The effect of the 2 drugs was superimposable in GH/PRL co-secreting tumors (-42.1% vs -44.8%), where SST1 and D2R had a higher expression compared with the pure GH-secreting tumors (P = 0.020 and P = 0.026). OCT was more effective than CAB in 8/23 cultures, while CAB was more effective than OCT in 3/23 (CAB+ group). In CAB+ tumors, SST1 expression was higher compared with the other groups (P = 0.034). At receiver operating characteristic (ROC) curve analysis, SST1 and D2R discriminated between GH and GH/PRL co-secretion (AUC 0.856, P = 0.013; AUC 0.822, P = 0.024). SST1 was the best predictor of CAB response (≥50% GH reduction, AUC 0.913, P = 0.006; 80% sensitivity, 94% specificity). OCT is 5% to 10% more effective than CAB in vitro. SST1 mRNA expression can represent a reliable marker of GH/PRL co-secreting tumors showing a preferential response to CAB treatment.

Development of a Connected Sensor System in Colorectal Surgery: User-Centered Design Case Study.

BackgroundA successful innovative medical device is not only technically challenging to develop but must also be readily usable to be integrated into health care professionals’ daily practice. Through a user-centered design (UCD) approach, usability can be improved. However, this type of approach is not widely implemented from the early stages of medical device development.ObjectiveThe case study presented here shows how UCD may be applied at the very early stage of the design of a disruptive medical device used in a complex hospital environment, while no functional device is available yet. The device under study is a connected sensor system to detect colorectal anastomotic leakage, the most detrimental complication following colorectal surgery, which has a high medical cost. We also aimed to provide usability guidelines for the initial design of other innovative medical devices.MethodsUCD was implemented by actively involving health care professionals and all the industrial partners of the project. The methodology was conducted in 2 European hospitals: Grenoble-Alpes University Hospital (France) and Erasmus Medical Center Rotterdam (the Netherlands). A total of 6 elective colorectal procedures and 5 ward shifts were observed. In total, 4 workshops were conducted with project partners and clinicians. A formative evaluation was performed based on 5 usability tests using nonfunctional prototype systems. The case study was completed within 12 months.ResultsFunctional specifications were defined for the various components of the medical device: device weight, size, design, device attachment, and display module. These specifications consider the future integration of the medical device into current clinical practice (for use in an operating room and patient follow-up inside the hospital) and interactions between surgeons, nurses, nurse assistants, and patients. By avoiding irrelevant technical development, this approach helps to promote cost-effective design.ConclusionsThis paper presents the successful deployment over 12 months of a UCD methodology for the design of an innovative medical device during its early development phase. To help in reusing this methodology to design other innovative medical devices, we suggested best practices based on this case.

Radiological Patterns of Uveal Melanoma Liver Metastases in Correlation to Genetic Status.

Simple SummaryPatients with uveal melanoma develop metastases that almost always affect the liver. These liver metastases can have as different metastatic patterns. In this study we investigated the role of the mutation status of the primary tumor in this metastatic process. Mutations in BAP1 or SF3B1 did not correlate with a specific hepatic metastatic pattern, whereas chromosome 1p loss and 8p loss were much more frequent in the primary uveal melanomas of patients who eventually develop miliary metastases in comparison to patients who develop single solitary hepatic metastases. Future endeavors could focus on discovering additional (genetic) factors which influence the propagation and development of hepatic metastases in UM.This study reports the role played by the mutation status of Uveal Melanoma (UM) in relation to hepatic metastatic patterns as seen on imaging modalities. Radiological images were obtained from 123 patients treated at the Erasmus Medical Center Rotterdam or the Rotterdam Eye Hospital. Radiological images were derived from either computed tomography or magnetic resonance imaging. Hepatic metastatic patterns were classified by counting the number of metastases found in the liver. Miliary metastatic pattern (innumerable small metastases in the entire liver) was analyzed separately. Mutation status was determined in 85 patients. Median disease-free survival (DFS) and survival with metastases differed significantly between each of the metastatic patterns (respectively, p = 0.009, p < 0.001), both in favor of patients with less hepatic metastases. The mutation status of the primary tumor was not correlated with any hepatic tumor profiles (p = 0.296). Of the patients who had a solitary metastasis (n = 18), 11 originated from a primary BAP1-mutated tumors and one from a primary SF3B1-mutated tumor. Of the patients who had a miliary metastasis pattern (n = 24), 17 had a primary BAP1-mutated tumor and two had a primary SF3B1-mutated tumor. Chromosome 8p loss was significantly more in patients with more metastases (p = 0.045). Moreover, the primary UMs of patients with miliary metastases harbored more chromosome 8p and 1p loss, compared to patients with single solitary metastasis (p = 0.035 and p = 0.026, respectively). In conclusion, our study shows that there is an inverse correlation of the number of metastasis with the DFS and metastasized survival, indicating separate growth patterns. We also revealed that the number and type of metastases is irrelevant to the prognostic mutation status of the tumor, showing that both BAP1- and SF3B1-mutated UM can result in solitary and miliary metastases, indicating that other processes lay ground to the different metastatic patterns.

P213 Having Inflammatory Bowel Disease Negatively Impacts Household and Family Life

Abstract Background Inflammatory bowel disease (IBD) can have a major impact on different aspects of life. This study aimed to provide insight into the impact of IBD on household and/or family life, and to determine whether this differed between sex. Methods Between September and December 2020, adult IBD patients from the outpatient clinic of the Erasmus Medical Center (Rotterdam, the Netherlands) were invited to fill out a survey. A questionnaire was developed to measure the impact of IBD on functioning in the household and on family planning. Generic disability and work disability were measured with the IBD Disability Index (IBD-DI) and the Work Productivity and Activity Impairment Questionnaire (WPAI-IBD). Data were analysed using descriptive statistics and tests for independent groups. Results Of the 229 patients who participated (response rate 74%), 68% had Crohn’s disease, 69% was female and the median age was 38.0 years. Many patients experienced difficulties with domestic activities (55.0%), leisure (53.9%), parenting (50.6%), sexual activities (48.4%) and interpersonal relationships (39.1%) because of IBD in the past week. Furthermore, 32.7% of patients felt that IBD interfered with their desire to have children. Female sex was associated with more severe limitations in various aspects of household life, more interference in family planning and higher generic disability scores. Conclusion IBD had a markedly negative impact on household and/or family life in many patients. In order to optimize patient care, physicians need to be aware of household and family related difficulties and strive for a holistic treatment approach.

Effect of Steroids as an Adjunct to Surgical Treatment in Patients with Chronic Subdural Hematoma.

The role of steroids as an adjunct to surgery for chronic subdural hematoma (cSDH) remains unclear. We evaluated the effect of steroids as an adjunct to surgery on recurrence rates, complications, and mortality. We retrospectively collected data of 525 patients operated on for cSDH between January 2010 and April 2015 at the Amsterdam University Medical Centers and Erasmus Medical Center Rotterdam. Data from patients with and without steroid use as an adjunct to surgery were obtained from medical records and compared using the chi-square test, independent-samples t-test, and Mann-Whitney U test, where applicable. Associations between adjuvant steroid use and complications were analyzed with univariable (penalized likelihood) logistic regression analysis. Multi-variate logistic regression was performed to analyze the influence of adjuvant steroid use on recurrence. Propensity-score matching was used to assemble a cohort of patients with similar baseline characteristics. Two hundred seventy-eight of the 525 patients (53%) were treated with adjuvant steroids. Surgery for recurrences occurred less in patients of the steroid group (9% vs. 14%; odds ratio [OR] 0.57; 95% confidence interval [CI], 0.33-0.99), but the effect was not significant after correction for confounders (adjusted aOR, 0.59; 95% CI, 0.33-1.05). In the steroid group, delirium (10% vs. 3%; OR, 3.99; 95% CI, 1.72-9.29) and dysregulated glucose levels occurred more frequently (2% vs. 0%; OR, 11.81; 95% CI, 1.38-1542.79), but multi-variate analysis was not possible. After propensity-score matching, McNemar's chi-square test showed that adjuvant steroid use was not significantly associated with recurrence rate (p = 0.10). Steroids as an adjunct to surgery in patients with cSDH did not have a favorable effect on the recurrence rate in our data after controlling for confounders.

Cardiac biomarkers for cardiovascular risk prediction among women and men from the general population

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): the Erasmus Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Health Research and Development (ZonMw); Purpose To evaluate the sex-specific predictive value of two cardiac biomarkers; N-terminal pro B-type natriuretic peptide (NT-proBNP) and high sensitivity cardiac troponin T (hs-cTnT), alongside traditional cardiovascular risk factors, for 10-year cardiovascular risk prediction in general population. Methods A total of 5430 participants (mean age 68.1 years; 59.9% women) free of cardiovascular disease (CVD), with blood sample measurements between 1997 and 2001 were included. We developed a ‘base’ model using cardiovascular risk factors used in the Pooled Cohort Equation (includes age, sex, systolic blood pressure, treatment of hypertension, total and high-density lipoprotein cholesterol levels, smoking, and diabetes) and then extended the ‘base’ model with NT-proBNP or hs-cTnT. These models were developed for coronary heart disease (CHD), stroke, and heart failure (HF) and also for composite CVD outcomes. To evaluate biomarkers’ added predictive value, c-statistic, and net reclassification improvement index (NRI) for events and non-events were calculated. NRI was calculated using cutoffs of 5%, 7.5% and 20% to categorize participants as low, borderline, intermediate, or high risk. Results Adding NT-proBNP to the ‘base’ model significantly improved c-statistic for all outcomes (increases ranged between 0.012-0.047), with the largest improvement in HF [0.026 (95% CI, 0.013, 0.040) for women and 0.047 (95% CI, 0.026, 0.069) for men]. Adding hs-TnT to ‘base’ model increased the c-statistic for CHD in women by 0.040 (95% CI, 0.013, 0.067) and for HF in men by 0.032 (95% CI, 0.005, 0.059). Improvments in reclassification by both biomarkers were mostly limited to modest improvemetns in reclassification of non-events [largest non-event NRI for global CVD in women (NT-proBNP: 11.8%; hs-cTnT: 10.5%) and for HF in men (NT-proBNP: 9.6%; hs-cTnT: 8.4%)]. Conclusion NT-proBNP improved model performance for prediction of all cardiovascular outcomes, in particular for HF, beyond traditional risk factors for both women and men. Hs-cTnT showed modest added predictive value beyond traditional risk factors for CHD among women and for HF among men. Imropovements in reclassification by both biomarkers were modest and not clinically relevant. Improvements of 10-year risk predictions Events Adding NT-proBNP Adding troponin T Delta c-statistic* Event NRI, % Non-event NRI, % Delta c-statistic* Event NRI, % Non-event NRI, % WomenASCVD Global CVD 0.012 (0.004, 0.020) 0.018 (0.010, 0.026) -1.7 (-5.0, 1.5)-0.8 (-3.8, 2.2) 5.4 (3.5, 7.2)11.8 (9.6, 14.1) 0.028 (0.009, 0.048)0.025 (0.009, 0.040) -0.4 (-7.1, 6.2)2.9 (-2.4, 8.3) 6.9 (3.9, 9.9)10.5 (7.3, 13.8) MenASCVD Global CVD 0.016 (0.005, 0.027)0.023 (0.012, 0.033) 0.7 (-2.3, 3.7)-0.3 (-3.0, 2.4) 5.2 (3.2, 7.2)7.2 (4.9, 9.4) 0.007 (-0.002, 0.016)0.011 (0.000, 0.021) -1.1 (-5.0, 2.7)-1.6 (-6.0, 2.8) 4.0 (1.2, 6.9)6.4 (3.1, 9.7) ASCVD comprises coronary heart disease and stroke; Global CVD comprises coronary heart disease, stroke and heart failure.

Outcomes of surgical aortic valve replacement over three decades

ObjectiveThe study objective was to analyze temporal changes in baseline and procedural characteristics and long-term survival of patients undergoing surgical aortic valve replacement over a 30-year period. MethodsA retrospective analysis of patients undergoing surgical aortic valve replacement between 1987 and 2016 in the Erasmus Medical Center (Rotterdam, The Netherlands) was conducted. Patient baseline and procedural characteristics were analyzed in periods according to the date of surgical aortic valve replacement (period A: 1987-1996; B: 1997-2006; C: 2007-2016). Survival status was determined using the Dutch National Death Registry. Relative survival was obtained by comparing the survival after surgical aortic valve replacement with the survival of the age-, sex-, and year-matched general population. ResultsBetween 1987 and 2016, 4404 patients underwent SAVR. From period A to C, the mean age increased from 63.9 ± 11.2 years to 66.2 ± 12.3 years (P < .001), and the prevalence of diabetes mellitus, hypertension, hypercholesterolemia, previous myocardial infarction, and previous stroke at baseline increased (P values for trend for all < .001). The prevalence of concomitant procedures increased from 42.4% in period A to 48.3% in period C (P = .004). Bioprosthesis use increased significantly (18.8% in period A vs 67.1% in period C, P < .001). Mean survival after surgical aortic valve replacement was 13.8 years. Relative survival at 20 years in the overall cohort was 60.4% (95% confidence interval, 55.9-65.2) and 73.8% (95% confidence interval, 67.1-81.1) in patients undergoing isolated primary surgical aortic valve replacement. ConclusionsPatient complexity has been continuously increasing over the last 30 years, yet long-term survival after surgical aortic valve replacement remains high compared with the age-, sex-, and year-matched general population.

SIZE study: study protocol of a multicentre, randomised controlled trial to compare the effectiveness of an interarcuair decompression versus extended decompression in patients with intermittent neurogenic claudication caused by lumbar spinal stenosis

IntroductionIntermittent neurogenic claudication (INC) is often caused by lumbar spinal stenosis (LSS). Laminectomy is considered a frequently used surgical technique for LSS. Previous studies have shown that laminectomy can potentially...

1-9HYPERTENSION AND ATRIAL VOLTAGES AT ATRIAL APPENDAGES

Background: Hypertension has been linked with alterations of atrial electrophysiology, which related to the substrate of atrial fibrillation. However, atrial voltages at atrial appendages and their relationship with hypertension remain undiscovered. The study aimed to investigate atrial voltages at both right and left atrial appendages (RAA and LAA) and their correlations with hypertension in patients with underlying heart disease. Materials &amp; Methods: Subjects with ischemic and/or valvular heart disease undergoing cardiac surgery at Erasmus Medical Center Rotterdam were included. After the heart was exposed during open chest surgery, high-resolution epicardial mapping of the LAA and the RAA during sinus rhythm was performed before starting cardiopulmonary bypass. Custom-made software was used to measure atrial voltages. A history of hypertension was obtained from the electronic medical record before undergoing surgery. Results: Among 133 patients undergoing cardiac surgery, 88 patients (66%) had hypertension. Atrial voltages at the LAA were higher in hypertensive patients compared to non-hypertensive patients (median = 5.36 vs 3.59 p &lt; 0.05), also a correlation between hypertension and atrial voltages at the LAA was identified (r = 0.247, p &lt; 0.05). On the other hand, atrial voltages at the RAA were comparable between hypertensive and non-hypertensive patients (median = 4.30 vs 3.96, p &gt; 0.05), without any correlation was found between hypertension and atrial voltages at the RAA. Conclusions: Atrial voltages at the LAA are higher compared to the RAA within hypertensive patients. Hypertension is also correlated with higher atrial voltages at the LAA. High atrial voltages at the LAA might be associated with structural changes of the LAA impacted by systemic hypertension.

Long-term developmental effect of withholding parenteral nutrition in paediatric intensive care units: a 4-year follow-up of the PEPaNIC randomised controlled trial

The PEPaNIC randomised controlled trial, which recruited 1440 critically ill infants and children in 2012-15, showed that withholding parenteral nutrition for 1 week (late-parenteral nutrition), compared with early supplementation within 24 h of admission to the paediatric intensive care unit (early-parenteral nutrition), prevented infections, accelerated recovery, and improved neurocognitive development assessed 2 years later. Because several neurocognitive domains can only be thoroughly assessed from age 4 years onwards, we aimed to determine the effect of late-parenteral nutrition versus early-parenteral nutrition on physical, neurocognitive, and emotional and behavioural development 4 years after randomisation. This is a preplanned, blinded, 4-year follow-up study of participants included in the PEPaNIC trial (done at University Hospitals Leuven, Belgium; Erasmus Medical Centre Sophia Children's Hospital, Rotterdam, Netherlands; and Stollery Children's Hospital, Edmonton, AB, Canada) and of matched healthy children. Studied outcomes were anthropometrics; health status; parent-reported or caregiver-reported executive functions, and emotional and behavioural problems; and clinical tests for intelligence, visual-motor integration, alertness, motor coordination, and memory. Through multivariable linear and logistic regression analyses, after imputation for missing values (≤30%) and adjustment for risk factors, we investigated the effect of early-parenteral nutrition versus late-parenteral nutrition. This trial is registered with ClinicalTrials.gov, NCT01536275. Between March 8, 2016, and Nov 8, 2019, 684 children from the original PEPaNIC trial (356 from the late-parenteral nutrition group and 328 from the early-parenteral nutrition group) were assessed for neurocognitive development at 4-years follow-up. Compared with the control group (369 healthy children), children who had critical illness had lower height (β-estimate -2·11 [95% CI -3·15 to -1·06]; p<0·0001) and head circumference (-0·42 [-0·67 to -0·18]; p=0.00077); and worse health status (eg, hospital admission odds ratio 4·27 [95% CI 3·12 to 5·84]; p<0·0001), neurocognitive (eg, parent-reported or caregiver-reported total executive functioning β-estimate 3·57 [95% CI 1·95 to 5·18], p<0·0001; total intelligence quotient -7·35 [-9·31 to -5·39], p<0·0001), and parent-reported or caregiver-reported emotional and behavioural developmental outcomes (internalising 2·73 [1·19 to 4·28], p=0·00055; externalising 1·63 [0·19 to 3·08], p=0·027; and total behavioural problems 2·95 [1·44 to 4·46], p=0·00013), adjusted for risk factors. Outcomes were never worse in the late-parenteral nutrition group compared with the early-parenteral nutrition group, but patients in the late-parenteral nutrition group had fewer parent-reported or caregiver-reported internalising (β-estimate -1·88 [95% CI -3·69 to -0·07]; p=0·042), externalising (-1·73 [-3·43 to -0·03]; p=0·046), and total emotional and behavioural problems (-2·44 [-4·22 to -0·67]; p=0·0070) than patients who had received early-parenteral nutrition, after adjusting for risk factors, and were no longer different from healthy controls for these outcomes. Omitting early parenteral nutrition use for critically ill children did not adversely affect long-term outcomes 4 years after randomisation and protected against emotional and behavioural problems, further supporting the deimplementation of early parenteral nutrition. European Research Council, Methusalem, Flanders Institute for Science and Technology, Research Foundation Flanders, Sophia Foundation, Stichting Agis Zorginnovatie, Erasmus Trustfonds, and the European Society for Clinical Nutrition and Metabolism.

What Happens When You Administer Mesenchymal Stromal Cells During Normalthermic Machine Perfusion of Porcine Kidneys: Possible and Helpful, or not?

K Rozenberg 1, L Knijff 1, J M Sierra Parraga 2, L Lo Faro 1, M J Hoogduijn 2, C 2, J Hunter 1, R Ploeg 1&#x0D; &#x0D; Nuffield Department of Surgical Sciences, University of Oxford, Oxford, United Kingdom&#x0D; Department of Internal Medicine, Nephrology and Transplantation, Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands&#x0D; &#x0D; BackgroundDonation after circulatory death kidneys are widely used to increase the donor pool, despite their inferior quality. Normothermic machine perfusion (NMP) could provide a platform to assess organ viability prior to transplantation and offers the unique opportunity for active interventions to an isolated organ. Mesenchymal stromal cells (MSC) have been shown to possess potent anti-inflammatory and regenerative properties ameliorating ischaemia reperfusion injury. However, the most common delivery route of MSC is intravenous infusion, which is associated with off-target distribution. We aimed to determine the dose of MSC needed to allow successful homing in donor kidneys during NMP without adversely affecting renal perfusion dynamics.&#x0D; MethodsPorcine slaughterhouse kidneys with 20 min warm ischaemia were retrieved and underwent 3h hypothermic machine perfusion followed by NMP for 7h. An oxygenated, autologous blood-based solution containing albumin, electrolytes and nutrients was used as perfusate. Following 1h of NMP, either a vehicle, 2 x 106, 10 x 106 or 50 x 106 labelled (Qdots) porcine adipose derived MSC (n=3 per group) were injected into the cannulated renal artery. Physiological recordings were taken regularly. Perfusate, urine and biopsies were obtained for biomarker analysis and to locate MSC.&#x0D; ResultsNo difference was found in average renal blood flow (p=0.668), renal resistance (p=0.828) and urine production (p=0.307) between all MSC groups compared to control. Damage markers LDH and AST increased during NMP and remained similar between groups (p=0.816 and p=0.312). Confocal microscopy demonstrated mainly glomerular localization of MSC (Figure 1), but they were also observed in the capillary network around the tubules. Additionally, a significant percentage of localised MSC was observed in the glomeruli in the 10 and 50 million MSC groups compared to 2 million MSC (p=0.002 and p&lt;0.0001). No differences were observed between the 2 and 10 million MSCs group (p&gt;0.05). There is a significant increase in secreted inflammatory mediator PGE2 with time in all groups (P&lt;0.05).&#x0D; DiscussionAdministration of different doses of MSC to the donor kidneys during NMP is safe and feasible. MSC successfully homed in the glomeruli. This model provides us with the opportunity of getting a better insight in the interaction between MSC and injured donor kidney: how do MSC or their released secretome affect tissue integrity and renal function.

ERJ November Podcast: Macrolides in severe asthma.

As part of the November issue, the European Respiratory Journal presents the latest in its series of podcasts. Deputy Chief Editor James Chalmers interviews Sarah Hiles (University of Newcastle, Callaghan, Australia), Peter Gibson (University of Newcastle, Callaghan, and John Hunter Hospital, New Lambton Heights, Australia) and Guy Brusselle (Ghent University Hospital, Ghent, Belgium, and Erasmus Medical Center Rotterdam, Rotterdam, The Netherlands) about their individual patient data meta-analysis of the use of azithromycin in severe asthma published in this issue.

Different potencies of topical corticosteroids for a better treatment strategy in children with atopic dermatitis (the Rotterdam Eczema study): protocol for an observational cohort study with an embedded randomised open-label controlled trial

IntroductionTopical corticosteroids (TCS) of different potencies are the main treatment to control atopic dermatitis (AD). The Dutch guideline on AD for general practitioners (GPs) recommends a stepwise approach in which...

Clinical Manifestations, Prognosis, and Vaccination Status of Patients With Rubella Virus–Associated Uveitis

To assess the clinical and laboratory manifestations and vaccination status of uveitis patients positive for rubella virus (RV) in aqueous humor and investigate its relationship to Fuchs uveitis syndrome (FUS). Retrospective study of all uveitis patients, positive for RV in aqueous humor analysis (polymerase chain reaction [PCR] and/or Goldmann-Witmer coefficient [GWC]) between January 2010 and October 2016 at the ophthalmology departments in the Erasmus Medical Center (Rotterdam) and University Medical Center Utrecht. Outcomes of aqueous analyses of FUS patients during this period were assessed. We included 127 patients (144 eyes) positive for RV in aqueous fluid: 23 (20%) by PCR, 120 (97%) by GWC, and 16 (13%) by both. The average age at first presentation was 37 years. Patients typically complained of blurred vision and exhibited a combination of unilateral anterior uveitis, keratic precipitates, vitritis, and absence of posterior synechiae, but the classical FUS was observed in a minority. The main cause of untreatable visual loss was glaucoma. Cystoid macular edema (CME) before intraocular surgery was not encountered. None of the unilateral cases developed involvement of the other eye. None of the patients was vaccinated against RV. All FUS patients, except 2 (5%), were positive for RV. RV-associated uveitis and FUS are not exchangeable. Chronic anterior uveitis, vitritis, early development of cataract, and the absence of posterior synechiae and CME characterize RV-associated uveitis. Almost all FUS cases had documented intraocular RV infection, but only some of the patients with RV-associated uveitis presented with FUS.

Evaluation of effectiveness of the PlasmaJet surgical device in the treatment of advanced stage ovarian cancer (PlaComOv-study): study protocol of a randomized controlled trial in the Netherlands

BackgroundThe most important goal for survival benefit of advanced stage ovarian cancer is to surgically remove all visible tumour, because complete cytoreductive surgery (CCS) has been shown to be associated with prolonged survival.In a remarkable number of women, CCS is very challenging. Especially in women with many small metastases on the peritoneum and intestinal surface, conventional CCS with electrosurgery is not able to be “complete” in removing safely all visible tumour.In this randomized controlled trail (RCT) we investigate whether the use of the PlasmaJet Surgical Device increases the rate of CCS, and whether this indeed leads to a longer progression free and overall survival.The main research question is: does the use of the PlasmaJet Surgical Device in surgery for advanced stage ovarian cancer result in an increased number of complete cytoreductive surgeries when compared with conventional surgical techniques. Secondary study objectives are: 30-day morbidity, duration of surgery, blood loss, length of hospitalisation, Quality of Life, disease-free survival, overall survival, percentage colostomy, cost-effectiveness.MethodsThe study design is a multicentre single-blinded superiority RCT in two university and nine non-university hospitals in The Netherlands. Three hundred and thirty women undergoing cytoreductive surgery for advanced stage ovarian carcinoma (FIGO Stage IIIB-IV) will be randomized into two arms: use of the PlasmaJet (intervention group) versus the use of standard surgical instruments combined with electrocoagulation (control group). The primary outcome is the rate of complete cytoreductive surgery in both groups.Secondary study objectives are: 30-day morbidity, duration of surgery, blood loss, length of hospitalisation, Quality of Life, disease-free survival, overall survival, percentage colostomy, cost-effectiveness. Quality of life will be evaluated using validated questionnaires at baseline, at 1 and 6 months after surgery and at 1, 2, 3 and 4 years after surgery.DiscussionWe hypothesize the additional value of the use of the PlasmaJet in CCS for advanced stage epithelial ovarian cancer. More knowledge about efficacy, side effects, recurrence rates, cost effectiveness and pathology findings after using the PlasmaJet Device is advocated. This RCT may aid in this void.Trial registrationDutch Trial Register NTR6624. Registered 18 August 2017.Medical Ethical Committee approval number: NL62035.078.17 (Medical Ethical Committee Erasmus Medical Centre Rotterdam).

Sa1275 ENDOSCOPIC RESECTION OF ADVANCED AMPULLARY ADENOMAS: A SINGLE-CENTER 14 YEAR RETROSPECTIVE COHORT STUDY

Adenomas of the ampulla of Vater are rare. Endoscopic ampullectomy has been recognized as a safe and reliable treatment of selective tumors of the ampulla of Vater and is associated with lower morbidity and mortality rates than surgical resection. However, the success rates for endoscopic ampullectomy range from 42-92%, with recurrence described in up to 33%. Despite the increasing number of studies concerning endoscopic resection of ampullary tumors, data evaluating endoscopic resection of the more advanced ampullary adenomas are limited. We aimed to evaluate the technical success, complications and recurrence of endoscopic resection for treating patients with ampullary adenomas with intraductal extension (IEA), or with a lateral spreading growth pattern (LSA). Between January 2002 and November 2016 all patients referred to the Erasmus Medical Center Rotterdam, for endoscopic resection of an ampullary lesion were retrospectively identified. Cases were selected using ENDOBASE and our local PALGA database. We included patients with a histological diagnosis of adenoma. Endoscopic success was defined as complete excision of the adenoma, irrespective of the number of attempts, and in the absence of recurrence. All patients underwent endoscopic follow-up. We included 84 patients, 56 patients (67%) had an adenoma confined to the ampulla (ACA), 17 patients (20%) had an LSA and 11 patients (13%) were treated for adenomas that demonstrated growth pattern with intraductal extension. Fifty-four percent of patients were men and the median age was 67.6 years. The mean lesion size was 24.6mm (range 5-80) for patients with ACA, 34.8mm (range 23-50) for LSA and 16.3mm (range 10-20) for patients with an IEA (P=0.005) Complications occurred in 22 patients (26.2%), of which hemorrhage was most prevalent (11.9%), followed by perforation (8.3%). Complications were equally divided (P=0.528). The mean follow-up duration was 21.1 months (IQR 12-45.9) for ACA, 14.3 months (IQR 3.3-34.1) for LSA and 5.8 months (IQR 3.7-22.0) for IEA (P=0.043). Endoscopic resection was curative in 87.5% of patients with an ACA, 82.3% in patients with an LSA and in only 9.1% of patients with an IEA (P <0.001). Recurrence occurred in 9 patients (10.7%), 5 of them had a localized adenoma, 3 patients with an LSA and 1 patient with an IEA (P=0.875). Endoscopic ampullectomy is a safe and successful treatment in patients with an adenoma with or without a lateral spreading growth pattern. In case of an intraductal extended adenoma endoscopic success rates are significantly lower.

Anxiety, memories and coping in patients undergoing intracranial tumor surgery

ObjectivesThe diagnosis and the surgical removal of a brain tumor can have serious impact on the quality of life of a patient. The question rises, whether having more or just less memories of the procedure is better for coping with such an event. Furthermore, for preoperative information of future patients it is important to know how patients process their emotions and memories. The primary objective of this study was to investigate the link between preoperative anxiety, the perioperative experience and the quantity and quality of postoperative memories in patients who underwent intracranial tumor surgery. Patients and methodsThis study was a retrospective observational study; all patients who underwent intracranial tumor surgery at the Erasmus Medical Centre Rotterdam between January 1st 2014 and December 31st 2015 were identified. In May 2016, all patients who were not registered as deceased were sent a questionnaire about their anxieties, perceptions and memories of the perioperative period. ResultsIn total 476 patients were included. 272 patients responded, which resulted in a response rate of 57.14%. In the general anesthesia (GA) group there was a significant negative correlation between anxiety in the perioperative period and the quantity and quality of memories. In the awake craniotomy group, there was a significant negative correlation between anxiety after the operation and the quantity of memories. ConclusionPatients in the GA group who experienced anxiety in the perioperative period had less quantity and quality of memories and less patient satisfaction. Patients in the AC group who experienced anxiety after the operation had only a lower quantity of the memory; there was no correlation with patient satisfaction.