Search

Retinitis pigmentosa and Leber congenital amaurosis are inherited retinal dystrophies that can be caused by mutations in the Crumbs homolog 1 (CRB1) gene. CRB1 is required for organizing apical-basal polarity and adhesion between photoreceptors and Müller glial cells. CRB1 patient-derived induced pluripotent stem cells were differentiated into CRB1 retinal organoids that showed diminished expression of variant CRB1 protein observed by immunohistochemical analysis. Single-cell RNA sequencing revealed impact on, among others, the endosomal pathway and cell adhesion and migration in CRB1 patient-derived retinal organoids compared with isogenic controls. Adeno-associated viral (AAV) vector-mediated hCRB2 or hCRB1 gene augmentation in Müller glial and photoreceptor cells partially restored the histological phenotype and transcriptomic profile of CRB1 patient-derived retinal organoids. Altogether, we show proof-of-concept that AAV.hCRB1 or AAV.hCRB2 treatment improved the phenotype of CRB1 patient-derived retinal organoids, providing essential information for future gene therapy approaches for patients with mutations in the CRB1 gene.

Supplementary File S7. Predicted target genes

Purpose: The survival of patients with clear cell metastatic renal cell carcinoma (cc-mRCC) has improved substantially since the introduction of tyrosine kinase inhibitors (TKI). With the fact that TKIs interact with immune responses, we investigated whether polymorphisms of genes involved in immune checkpoints are related to the clinical outcome of cc-mRCC patients treated with sunitinib as first TKI.Experimental Design: Twenty-seven single-nucleotide polymorphisms (SNP) in CD274 (PD-L1), PDCD1 (PD-1), and CTLA-4 were tested for a possible association with progression-free survival (PFS) and overall survival (OS) in a discovery cohort of 550 sunitinib-treated cc-mRCC patients. SNPs with a significant association (P < 0.05) were tested in an independent validation cohort of 138 sunitinib-treated cc-mRCC patients. Finally, data of the discovery and validation cohort were pooled for meta-analysis.Results: CTLA-4 rs231775 and CD274 rs7866740 showed significant associations with OS in the discovery cohort after correction for age, gender, and Heng prognostic risk group [HR, 0.84; 95% confidence interval (CI), 0.72–0.98; P = 0.028, and HR, 0.73; 95% CI, 0.54–0.99; P = 0.047, respectively]. In the validation cohort, the associations of both SNPs with OS did not meet the significance threshold of P < 0.05. After meta-analysis, CTLA-4 rs231775 showed a significant association with OS (HR, 0.83; 95% CI, 0.72–0.95; P = 0.008). Patients with the GG genotype had longer OS (35.1 months) compared with patients with an AG (30.3 months) or AA genotype (24.3 months). No significant associations with PFS were found.Conclusions: The G-allele of rs231775 in the CTLA-4 gene is associated with an improved OS in sunitinib-treated cc-mRCC patients and could potentially be used as a prognostic biomarker. Clin Cancer Res; 24(10); 2350–6. ©2018 AACR.

Supplementary Table S1 Selected tagging SNPs Supplementary Figure S1 Kaplan-Meier plot for overall survival by genotype of CTLA-4 rs231775 in discovery cohort (A), validation cohort (B) and combined cohort (C). Supplementary Figure S2 The association of CTLA-4 rs231775 with CTLA-4 gene expression in multiple tissues (A) and in testis tissue (B, p=1.0Ã-10-7) using data from the Genotype-Tissue Expression (GTEx) dataset. Supplementary Figure S3 The survival curve shows the association of CTLA-4 gene expression with overall survival in patients with clear cell renal cell carcinoma (p=0.00255) through OncoLnc, which links The Cancer Genome Atlas (TCGA) survival data to mRNA expression levels (23). (low: lower 50 percentile, high: upper 50 percentile).

Contains fulltext : 290958.pdf (Publisher’s version ) (Open Access) Hepatotoxicity is a serious adverse drug reaction related to methotrexate (MTX). However, the cause of drug-induced liver injury (DILI) is still unclear and unpredictable. Genetic risk factors may predispose for MTX-DILI. Therefore, we conducted a nested case-control genome-wide association study to explore genetic risk factors associated with MTX-DILI. Seven international groups contributed blood samples and data of patients with rheumatoid arthritis who used MTX. MTX-DILI was defined as an alanine aminotransferase (ALT) level of at least three times the upper limit of normal (ULN), to increase contrast controls ALT levels did not raise above two times the ULN. Per study site, control subjects and patients with MTX-DILI (ratio 3:1) were matched for age, gender, and duration of MTX use. Patients were genotyped using Illumina GSA MD-24v1-0 and data were imputed using the 1000 Genomes reference panel. Single-nucleotide polymorphisms (SNPs) were analyzed using an additive genetic model, corrected for sex, country, and age. A P-value of ≤ 5 × 10(-8) was considered significant, whereas a P-value of ≤ 5 × 10(-6) was considered suggestive. A total of 108 MTX-DILI cases and 311 controls were included for association analysis. None of the SNPs were significantly associated with MTX-DILI. However, we found seven suggestive genetic variants associated with MTX-DILI (P-values 7.43 × 10(-8) to 4.86 × 10(-6) ). Of those, five SNPs were in the intronic protein-coding regions of FTCDNL1, BCOR, FGF14, RBMS3, and PFDN4/DOK5. Investigation of candidates SPATA9 (rs72783407), PLCG2 (rs60427389), RAVER2 (rs72675408), JAK1 (rs72675451), PTPN2 (rs2476601), MTHFR C677T (rs1801133), and into the HLA region did not show significant findings. No genetic variants associated with MTX-DILI were found, whereas suggestive SNPs need further investigation. 01 april 2023

Background The size of the margin strongly influences the required sample size in non-inferiority and equivalence trials. What is sometimes ignored, however, is that for trials with binary outcomes, the scale of the margin – risk difference, risk ratio or odds ratio – also has a large impact on power and thus on sample size requirement. When considering several scales at the design stage of a trial, these sample size consequences should be taken into account. Sometimes, changing the scale may be needed at a later stage of a trial, for example, when the event proportion in the control arm turns out different from expected. Also after completion of a trial, a switch to another scale is sometimes made, for example, when using a regression model in a secondary analysis or when combining study results in a meta-analysis that requires unifying scales. The exact consequences of such switches are currently unknown. Methods and Results This article first outlines sample size consequences for different choices of analysis scale at the design stage of a trial. We add a new result on sample size requirement comparing the risk difference scale with the risk ratio scale. Then, we study two different approaches to changing the analysis scale after the trial has commenced: (1) mapping the original non-inferiority margin using the event proportion in the control arm that was anticipated at the design stage or (2) mapping the original non-inferiority margin using the observed event proportion in the control arm. We use simulations to illustrate consequences on type I and type II error rates. Methods are illustrated on the INES trial, a non-inferiority trial that compared single birth rates in subfertile couples after different fertility treatments. Our results demonstrate large differences in required sample size when choosing between risk difference, risk ratio and odds ratio scales at the design stage of non-inferiority trials. In some cases, the sample size requirement is twice as large on one scale compared with another. Changing the scale after commencing the trial using anticipated proportions mainly impacts type II error rate, whereas switching using observed proportions is not advised due to not maintaining type I error rate. Differences were more pronounced with larger margins. Conclusions Trialists should be aware that the analysis scale can have large impact on type I and type II error rates in non-inferiority trials.

Primary bone diffuse large B-cell lymphoma (PB-DLBCL) is a rare extranodal lymphoma subtype. This retrospective study elucidates the currently unknown genetic background of a large clinically well-annotated cohort of DLBCLwith osseous localizations (O-DLBCL), including PB-DLBCL. A total of 103 patients with O-DLBCL were included and compared with 63 (extra)nodal non-osseous (NO)-DLBCLs with germinal center B-cell phenotype (NO-DLBCL-GCB). Cell-of-origin was determined by immunohistochemistry and gene-expression profiling (GEP) using (extended)-Nano-String/Lymph2Cx analysis. Mutational profileswere identifiedwith targeted next-generation deep sequencing, including 52 B-cell lymphoma-relevant genes. O-DLBCLs, including 34 PB-DLBCLs, were predominantly classified as GCB phenotype based on immunohistochemistry (74%) and NanoString analysis (88%). Unsupervised hierarchical clustering of an extended-NanoString/Lymph2Cx revealed significantly different GEP clusters for PB-DLBCL as opposed to NO-DLBCL-GCB (P < .001). Expression levels of 23 genes of 2 different targeted GEP panels indicated a centrocyte-like phenotype for PB-DLBCL, whereas NO-DLBCL-GCB exhibited a centroblast-like constitution. PB-DLBCL had significantly more frequent mutations in four GCB-associated genes (ie, B2M, EZH2, IRF8, TNFRSF14) comparedwithNO-DLBCL-GCB (P = .031, P = .010, P = .047, and P = .003, respectively). PB-DLBCL, with its corresponding specific mutational profile, was significantly associated with a superior survival compared with equivalent Ann Arbor limited-stage I/II NO-DLBCL-GCB (P = .016). This study is the first to show that PB-DLBCL is characterized by a GCB phenotype, with a centrocyte-like GEP pattern and a GCB-associated mutational profile (both involved in immune surveillance) and a favorable prognosis. These novel biology-associated features provide evidence that PB-DLBCL represents a distinct extranodal DLBCL entity, and its specific mutational landscape offers potential for targeted therapies (eg, EZH2 inhibitors).

BackgroundGenome-wide association studies among European populations have identified four single nucleotide polymorphisms (SNPs) in genes involved in vitamin D transport and metabolism affecting 25-hydroxyvitamin D [25(OH)D] concentration: rs2282679 in GC, rs6013897 near CYP24A1, rs10741657 near CYP2R1, and rs12785878 near DHCR7. It is, however, unknown whether the association with 25(OH)D can also be observed in a Chinese population living in the Netherlands.MethodsObservational study. Analyses were performed under an additive (univariate and multivariate) and genotypic model using logistic regression.ResultsThe C allele (minor allele frequency 0.28) of rs2282679 in GC was associated with vitamin D deficiency as defined by the Health Council of the Netherlands: 25(OH)D ConclusionOur findings suggest that, apart from sun exposure, lifestyle, and environmental factors, a common variant of GC may be associated with vitamin D deficiency.

Background: Pain is common in hand osteoarthritis (OA) and multiple types may occur. We investigated the prevalence, associated patient characteristics, influence on health-related quality of life (HR-QoL) and response to anti-inflammatory treatment of neuropathic-like pain in inflammatory hand OA. Methods: Data were analysed from a 6-week, randomized, double-blind, placebo-controlled trial investigating prednisolone treatment in 92 patients with painful inflammatory hand OA. Neuropathic-like pain was measured with the painDETECT questionnaire. Associations between baseline characteristics and baseline neuropathic-like pain were analysed with ordinal logistic regression, association of baseline neuropathic-like pain symptoms with baseline HR-QoL with linear regression, painDETECT and visual analogue scale (VAS) change from baseline to week 6 and interaction of painDETECT with prednisolone efficacy on VAS pain change from baseline to week 6 with generalized estimating equations (GEE). Results: Of 91 patients (79% female, mean age 64) with complete painDETECT data at baseline, 53% were unlikely to have neuropathic-like pain, 31% were indeterminate and 16% were likely to have neuropathic-like pain. Neuropathic-like pain was associated with female sex, less radiographic damage and more comorbidities. Patients with neuropathic-like pain had lower HR-QoL (PCS-6.5 [95% CI −10.4 to −2.6]) than those without. Neuropathic-like pain symptoms remained under prednisolone treatment and no interaction was seen between painDETECT and prednisolone efficacy on VAS pain. Conclusions: In this study, 16% of inflammatory hand OA patients had neuropathic-like pain. They were more often female, had more comorbidities and had lower QoL than those without. Neuropathic-like pain symptoms remained despite prednisolone treatment and did not seem to affect the outcome of prednisolone treatment. Significance: Pain is the dominant symptom in hand OA, with an unclear aetiology. In this study, we found that neuropathic-like pain may play a role in hand OA, that it showed associations with female sex, younger age and more comorbidities and that it lowered health-related quality of life in hand OA. Neuropathic-like pain in hand OA seems resistant to prednisolone therapy but did not seem to interfere with the treatment of inflammatory pain with prednisolone.

Objectives Tonsillectomy and adenoidectomy in children are controversial subjects with large regional variation in surgical rates, partly explained by cultural differences and lack of high‐quality evidence on indications for surgery. A quality of care cycle was executed on this topic in the Netherlands. The objective of this study was to estimate changes in healthcare utilisation for paediatric tonsil surgery in the Netherlands. Methods Population‐based data on tonsillectomies and adenoidectomies in children up to age 10 were retrieved retrospectively from Dutch administrative databases between 2005 and 2018. A change point analysis was performed to detect the most pivotal change point in surgical rates. We performed univariate analyses to compare surgical patients’ characteristics before and after the pivotalpoint . Impact on healthcare budget and societal costs were estimated using current prices and data from cost‐effectiveness analyses. Results The annual number of adenotonsillectomies reduced by 10 952 procedures (−39%; from 129 per 10 000 children to 87 per 10 000 children) between 2005 and 2018, and the number of adenoidectomies by 14 757 procedures (−49%; from 138 per 10 000 children to 78 per 10 000 children). The most pivotal change point was observed around 2012, accompanied by small changes in patient selection for surgery before and after 2012. An estimated €5.3 million per year was saved on the healthcare budget and €10.4 million per year on societal costs. Conclusion The quality of care cycle resulted in fewer operations, with a concomitant reduction of costs. We suggest that part of these savings be invested in new research to maintain the quality of care cycle.

Applying a face mask could provoke a trigeminocardiac reflex. We compared the effect of applying bi-nasal prongs with a face mask on breathing and heart rate of preterm infants at birth.In a retrospective matched-pairs study of infants32 weeks of gestation, the use of bi-nasal prongs for respiratory support at birth was compared to the use of a face mask. Infants who were initially breathing at birth and subsequently received respiratory support were matched for gestational age (±4 days), birth weight (±300 g), general anaesthesia and gender. Breathing, heart rate and other parameters were collected before and after interface application and in the first 5 min thereafter.In total, 130 infants were included (n = 65 bi-nasal prongs, n = 65 face mask) with a median (IQR) gestational age of 27Apnoea and bradycardia occurred often after applying either bi-nasal prongs or a face mask on the face for respiratory support in preterm infants at birth.

Plausibility is a formalization of exact tests for parametric models and generalizes procedures such as Fisher’s exact test. The resulting tests are based on cumulative probabilities of the probability density function and evaluate consistency with a parametric family while providing exact control of the α level for finite sample size. Model comparisons are inefficient in this approach. We generalize plausibility by incorporating weighing which allows to perform model comparisons. We show that one weighing scheme is asymptotically equivalent to the likelihood ratio test (LRT) and has finite sample guarantees for the test size under the null hypothesis unlike the LRT. We confirm theoretical properties in simulations that mimic the data set of our data application. We apply the method to a retinoblastoma data set and demonstrate a parent-of-origin effect. Weighted plausibility also has applications in high-dimensional data analysis and P -values for penalized regression models can be derived. We demonstrate superior performance as compared to a data-splitting procedure in a simulation study. We apply weighted plausibility to a high-dimensional gene expression, case-control prostate cancer data set. We discuss the flexibility of the approach by relating weighted plausibility to targeted learning, the bootstrap, and sparsity selection.

PurposeProvide up-to-date insight in incidence of retinopathy of prematurity (ROP), logistics of screening and treatment in the Netherlands and influence of the new national ROP guideline in which more stringent screening criteria were implemented and the early treatment for ROP criteria (ETROP) were emphasised.MethodsMulticentre prospective nationwide study including all preterm infants, born in the Netherlands in 2017, and considered eligible for ROP screening. Anonymised data from ophthalmologists and paediatricians were merged. Outcome data were compared with the first national ROP inventory (NEDROP-1, 2009).ResultsIn 2017, 1492 infants were live born with gestational age (GA) ConclusionThe overall ROP incidence expressed as a percentage, remained stable but the number of infants that developed severe ROP nearly doubled. A near one-third reduction in screened infants shows satisfactory implementation of the new screening criteria. A notable decrease in retinal detachment delineates improved treatment outcome.

Simple Summary Uveal melanoma (UM) is a rare ocular malignancy that often gives rise to metastases. Tumours with an inflammatory phenotype have an especially bad prognosis. As an increased HLA expression and the presence of tumour-infiltrating lymphocytes and macrophages may be regulated by miRNAs, we set out to investigate whether any miRNAs are associated with inflammatory parameters in this malignancy. Some miRNAs were increased in UM with a high HLA expression and high T cell numbers, while others were decreased, showing two opposing patterns; however, both patterns were related to the tumour’s chromosome 3/BAP1 status. We conclude that specific miRNAs are related to the inflammatory phenotype and that these are differentially expressed between disomy 3/BAP1-positive versus monosomy 3/BAP1-negative UM. Abstract MicroRNAs are known to play a role in the regulation of inflammation. As a high HLA Class I expression is associated with a bad prognosis in UM, we set out to determine whether any miRNAs were related to a high HLA Class I expression and inflammation. We also determined whether such miRNAs were related to the UM’s genetic status. The expression of 125 miRNAs was determined in 64 primary UM from Leiden. Similarly, the mRNA expression of HLA-A, HLA-B, TAP1, BAP1, and immune cell markers was obtained. Expression levels of 24 of the 125 miRNAs correlated with expression of at least three out of four HLA Class I probes. Four miRNAs showed a positive correlation with HLA expression and infiltration with leukocytes, 20 a negative pattern. In the first group, high miRNA levels correlated with chromosome 3 loss/reduced BAP1 mRNA expression, in the second group low miRNA levels. The positive associations between miRNA-22 and miRNA-155 with HLA Class I were confirmed in the TCGA study and Rotterdam cohort, and with TAP1 in the Rotterdam data set; the negative associations between miRNA-125b2 and miRNA-211 and HLA-A, TAP1, and CD4 were confirmed in the Rotterdam set. We demonstrate two patterns: miRNAs can either be related to a high or a low HLA Class I/TAP1 expression and the presence of infiltrating lymphocytes and macrophages. However, both patterns were associated with chromosome 3/BAP1 status, which suggests a role for BAP1 loss in the regulation of HLA expression and inflammation in UM through miRNAs.

Objectives Data on normal mandibular development in the infant is lacking though essential to understand normal growth patterns and to discriminate abnormal growth. The aim of this study was to provide normal linear measurements of the mandible using computed tomography performed in infants from 0 to 2 years of age. Material and methods 3D voxel software was used to calculate mandibular body length, mandibular ramus length, bicondylar width, bigonial width and the gonial angle. Intra- and inter-rater reliability was assessed for these measurements. They were found to be sufficient for all distances; intra-class correlation coefficients were all above 0.9. Regression analysis for growth modelling was performed. Results In this multi-centre retrospective study, 109 CT scans were found eligible that were performed for various reasons (e.g. trauma, craniosynostosis, craniofacial abscesses). Craniosynostosis patients had larger mandibular measurements compared to non-craniosynostosis patients and were therefore excluded. Fifty-one CT scans were analysed. Conclusions Analysis showed that the mandible increases more in size vertically (the mandibular ramus) than horizontally (the mandibular body). Most of the mandibular growth occurs in the first 6 months. Clinical relevance These growth models provide insight into normal mandibular development in the first 2 years of life. This reference data facilitates discrimination between normal and abnormal mandibular growth.

Monitoring the density of corneal endothelial cells (CEC) is essential in the management of corneal diseases. Its manual calculation is time consuming and prone to errors. U-Net, a neural network for biomedical image segmentation, has shown promising results in the automated segmentation of images of healthy corneas and good quality. The purpose of this study was to assess its performance in “real-world” CEC images (variable quality, different ophthalmologic diseases). The outcome measures were: precision and recall of the extraction of CEC, correctness of CEC density estimation, detection of ungradable images. A classical approach based on grayscale morphology and water shedding was pursued for comparison. There was good agreement between the automated image analysis and the manual annotation from the U-Net. R-square from Pearson’s correlation was 0.96. Recall of CEC averaged 0.34 and precision 0.84. The U-Net correctly predicted the CEC density in a large set of images of healthy and diseased corneas, including images of poor quality. It robustly ignored image regions with poor visibility of CEC. The classical approach, however, did not provide acceptable results. R-square from Pearson’s correlation with the ground truth was as low as 0.35.

In klinischen Studien bestehen im Vergleich zur klinischen Routine hohere Anforderungen, was einen zeitlichen Mehraufwand bedingt. Ziel dieser Arbeit ist die vollumfangliche Zeiterfassung an den deutschen ophthalmologischen Studienzentren. Mit 3 Fragebogen wurden bei den Mitgliedern der „Arbeitsgemeinschaft DOG Klinische Studienzentren“ der geschatzte Zeitaufwand fur die studienbezogenen Tatigkeiten, fur die Administration und prospektiv die tatsachliche Verwendung der Arbeitszeit abgefragt. Fur Letzteres wurde von jedem Mitarbeiter 3 Wochen lang zu jeder vollen Stunde ein Fragebogen ausgefullt („work sampling“). Die Fragebogen wurden von 9 der 11 angefragten Zentren ausgefullt. Insgesamt wurden 5504 Arbeitsstunden protokolliert. An einem durchschnittlichen Arbeitstag betrug der mittlere Aufwand fur Dokumentation und Administration jeweils 4 h. Signifikant waren auch operative Eingriffe (2,8 h), augenarztliche Untersuchungen (2,5 h) und Einwilligungsgesprache (1,5 h). Die protokollierte Dauer von Visusmessung, Einwilligung und Dokumentationen passte gut zu den Angaben aus den Fragebogen. Operative Eingriffe, augenarztliche Untersuchungen und die Handhabung von Bioproben wurden in der Dauer unterschatzt. Ein erheblicher Teil des Zeitaufwandes fallt fur Dokumentation an. Administrative Aufgaben sind ahnlich bedeutsam. Der uberraschend hohe Zeitbedarf fur operative Eingriffe, Untersuchungen und Handhabung von Bioproben resultiert wahrscheinlich aus Tatigkeiten zur Vor- und Nachbereitung, was im Kontext einer Vollkostenrechnung berucksichtigt werden muss. Viele administrative Tatigkeiten lassen sich zudem nicht ausreichend uber „case payments“ abbilden, sodass Zusatzvergutungen fur den kostendeckenden Betrieb eines ophthalmologischen Studienzentrums erforderlich sind.

Background: Voice outcome was assessed in patients with extended T1 and limited T2 glottic carcinoma, treated with a unilateral type III or a bilateral type II resection according to the European Laryngological Society (ELS) classification. Methods: Objective evaluation (acoustic and aerodynamic parameters), perceptual evaluation (GRBAS), and patients' self-assessment (voice handicap index [VHI]) were performed before and 1 year after treatment. Results were evaluated according to ELS resection type and the involvement of the anterior commissure. Results: The majority of voice parameters in all resection subgroups showed an improvement of the mean score 1 year postoperatively. Grade of dysphonia varied between 1.15 and 1.66 postoperatively and VHI score varied from 23.3 to 24.5. Conclusion: Voice outcome after ELS unilateral type III or a bilateral type II resection for extended T1 and limited T2 glottic carcinoma is good with mild to very moderate perceptive dysphonia and low self-reported voice impairment.

Objective: To validate whether serum Neurofilament Light-chain (NfL) levels correlate with disease severity in CADASIL, and to determine whether serum NfL predicts disease progression and survival. Methods: Fourty-one (pre-) manifest individuals with CADASIL causing NOTCH3 mutations and 22 healthy controls were recruited from CADASIL families. At baseline, MRI-lesion load and clinical severity was determined and serum was stored. Disease progression was measured in 30/41 patients at 7-year follow-up, and survival of all individuals was determined at 17-year follow-up. Serum NfL levels were quantified using an ultra-sensitive molecule array. Generalized estimated equation regression (GEE) was used to analyze association between serum NfL, MRI-lesion load, disease severity, and disease progression. With GEE-based Cox regression, survival was analyzed. Results: At baseline, serum NfL levels correlated with MRI-lesion load [lacune count (s = 0.64, P = 0.002), brain atrophy (r = −0.50, P = 0.001), and microbleed count (s = 0.48, P = 0.044)], cognition [CAMCOG (s = −0.45, P = 0.010), MMSE (r = −0.61, P = 0.003), GIT (r = −0.61, P

The PvuII (rs2234693) Single Nucleotide Polymorphism (SNP) in the gene coding for the estrogen receptor-1 (ESR1), has been found associated with outcome in tamoxifen treated patients with early hormone-receptor positive breast cancer. However, it remains unclear whether this SNP is a predictive marker for tamoxifen efficacy or a prognostic marker for breast cancer outcome. The aim of this study was to examine the prognostic potential of this SNP in postmenopausal early breast cancer patients treated with adjuvant exemestane. Dutch postmenopausal patients randomised to 5 years of adjuvant exemestane of whom tissue was available (N = 807) were selected from the Tamoxifen Exemestane Adjuvant Multinational (TEAM) trial database. The SNP rs2234693 in the ESR1 gene was genotyped on DNA from formalin-fixed paraffin embedded (FFPE) tumor tissue using Taqman assays and related to the primary endpoint disease-free survival (DFS) and secondary endpoint overall survival (OS). Survival analyses were performed using Cox regression analysis. In total 805 patients were included in the analyses (median follow up of 5.22 years) and genotypes were obtained in 97% of the samples. The variant T allele of PvuII in ESR1 (rs2234693) was associated with a better DFS (hazard ratio (HR) 0.689, 95% confidence interval (CI) 0.480–0.989, P = 0.044) in univariate analysis only, and a better OS in both univariate (HR 0.616, 95%, CI 0.411–0.923, P = 0.019) and multivariate analyses (HR 0.571, 95% CI 0.380–0.856, P = 0.007), consistent with a prognostic rather than a predictive drug response effect. Variation of PvuII in the ESR1 gene is related to OS in postmenopausal, early HR + breast cancer patients treated with exemestane in the TEAM study. Variation in the ESR1 gene may therefore be a prognostic marker of early breast cancer survival, and warrants further research.

IntroductionOutcomes of surgery for Ménière’s disease (MD) remain discordant. Recently, a new surgical procedure in which the endolymphatic duct is clipped was proposed. To date, only one prospective trial assessing this technique was published, yielding promising results. This protocol describes a prospective, double-blinded, randomised controlled trial that will be carried out to assess the effectiveness of this surgical intervention.MethodsEighty-four patients with intractable MD will be recruited from 13 hospitals in the Netherlands. Intraoperatively, randomisation will determine whether endolymphatic duct blockage (EDB) or endolymphatic sac decompression (ESD) will be performed. Randomisation will be 1:1 stratified for gender and duration of MD (recent-onset versus mature MD). All participants receive vestibular rehabilitation after surgery. Patients are followed up during 1 year after surgery. Follow-up visits will take place at 1 week, 3 months, 6 months and 12 months after surgery. The main study endpoint is proportion of patients who are free of vertigo spells at 12 months postoperatively. Secondary parameters include cumulative number of vertigo bouts, co-intervention, tinnitus, hearing, quality of life, cost effectiveness and a budget impact analysis. Total duration of the study is 4 years.AnalysisThe primary analysis will follow the intention-to-treat principle. For the primary outcome, a χ2 test will be performed. Secondary outcomes will be analysed using a linear mixed model (EDB versus decompression group) at the different time measurement point.Ethics and disseminationThis study was reviewed and approved by a board of specialists before funding was obtained, as well as by the Medical Research Ethics Committee Leiden-The Hague-Delft and the boards of all participating centres. Results of this study will be published in international peer-reviewed scientific journals and will be presented on (inter)national scientific conferences and meetings.Trial registration numbersNL9095 and ISRCTN12074571; Pre-Results.

This study describes the complication rate and use of autologous and/or homologous cartilage in a large 20-year cohort of septo(rhino)plasty surgeries in a Dutch hospital, in relation to postoperative complications of septo(rhino)plasty surgery described in previous studies. A retrospective medical chart review was conducted. 2606 patients, mean age 34.7 (± 13.2) and 59.9% male, underwent primary or revision septo(rhino)plasty surgery from 01/01/1999 to 01/09/2019. Follow-up was known in 1384 of 2606 patients (53.1%) with a mean duration of 47.5 months. Complication registration was complete for 1774 patients. The overall complication rate was 270 out of 1774 (15.2%). The use of autologous costal cartilage (ACC) was a risk factor for overall complication with an odds ratio (OR) of 11.1 (95% CI 0.03–0.30; P

Objectives Neuropsychiatric symptoms (NPS) are very common in older patients with dementia. There is increasing evidence that hypoperfusion of the brain plays a role in the development of NPS. The aim of this study is to assess whether there is an association between low systolic blood pressure (SBP) and NPS and if NPS are more prevalent in older people with dementia using antihypertensive medication. Methods We studied the baseline data from participants in the Communication, Systematic pain treatment, Medication review, Organized activities and Safety study, a multicenter clustered trial with 765 participants from 72 nursing home units from 37 nursing homes in Norway. SBP (lowest quartile vs rest) and use of antihypertensive medication were predictors and Neuropsychiatric Inventory—Nursing Home version (NPI-NH) score (total and clusters) was the outcome. Missing data were imputed, except for missing data in predictors. We used a mixed model analysis adjusted for age, sex and Minimal Mental State Examination (MMSE) score. In a sensitivity analysis, continuous SBP values were used. Results In total, 412 patients were included with a mean age of 86.9 years, 53.9% had a MMSE score of

Objective: To improve the interpretation of the Knee injury and Osteoarthritis Outcome Score (KOOS) in individual patients, we explored associations with age, sex, BMI, history of knee injury and presence of clinical knee osteoarthritis, and developed percentile curves.Methods: We used cross-sectional data of middle-aged individuals from the population-based Netherlands Epidemiology of Obesity (NEO) study. Clinical knee osteoarthritis was defined using the ACR classification criteria. KOOS scores were handled according to the manual (zero = extreme problems, 100 = no problems). Patient characteristics associated with KOOS were explored using ordered logistic regression, and sex and body mass index (BMI)-specific percentile curves were developed using quantile regression with fractional polynomials. The curves were applied as a benchmark for comparison of KOOS scores of participants with knee osteoarthritis and comorbidities.Results: The population consisted of 6,643 participants (56% women, mean (SD) age 56(6) years). Population-based KOOS subscale scores (median; interquartile range) near optimum: pain (100;94-100), symptoms (96;86-100), ADL function (100;96-100), sport/recreation function (100;80-100), quality of life (100;75-100). Worse KOOS scores were observed in women and in participants with higher BMI. Clinical knee osteoarthritis was defined in 15% of participants, and was, in comparison to other patient characteristics, associated with the highest odds of worse KOOS scores. Furthermore, presence of any comorbidity and cardiovascular disease specifically, was associated with worse KOOS scores, particularly in women.Conclusions: In the middle-aged Dutch population KOOS scores were generally good, but worse in women and with higher BMI. These percentile curves may be used as benchmarks in research and clinical practice. (c) 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

BACKGROUND: Infants with severe hemolytic disease of the fetus and newborn often require 1 or multiple intrauterine transfusions to treat fetal anemia. Intrauterine transfusions may have an inhibiting effect on fetal and neonatal erythropoiesis.OBJECTIVE: To quantify the effect of 1 or multiple intrauterine transfusions on the fetal erythropoiesis by assessing the fetal reticulocyte counts in a population with severe hemolytic disease of the fetus and newborn.STUDY DESIGN: This was an observational cohort study in infants admitted to the Leiden University Medical Center who received 1 or multiple intrauterine transfusions for hemolytic disease of the fetus and newborn caused by (Rh)D or Kell antibodies and were born between January 2005 and December 2018.RESULTS: A total of 235 patients were included, of whom 189 were patients with D-mediated hemolytic disease of the fetus and newborn and 46 with Kell-mediated hemolytic disease of the fetus and newborn. Absolute fetal reticulocyte count in D-mediated hemolytic disease of the fetus and newborn declined exponentially over the course of consecutive intrauterine transfusions, with a 62% decline after 1 intrauterine transfusion (95% confidence interval, 56-67). A similar exponential decline was observed in Kell-mediated hemolytic disease of the fetus and newborn, with 32% (95% confidence interval, 19-45) decline after 1 intrauterine transfusion. This decline was not associated with the varying gestational age at the time of the first intrauterine transfusion or the total number of intrauterine transfusions. The number of red blood cell transfusions for postnatal anemia was greater for infants with D and Kell-mediated hemolytic disease of the fetus and newborn with >2 intrauterine transfusions (median of 3 [interquartile range, 2-3] vs 2 [interquartile range, 1-3], P=.035, in D-mediated disease and median of 2 [interquartile range, 1-2] vs 1 [interquartile range, 1-1], P2 intrauterine transfusions less often required exchange transfusion in D-mediated hemolytic disease of the fetus and newborn (19/89 [21%] vs 31/100 [31%], P=.039), compared with infants with 1-2 intrauterine transfusions.CONCLUSION: Treatment with intrauterine transfusions causes an exponential decrease in fetal reticulocyte counts in both D- and Kell-mediated hemolytic disease of the fetus and newborn. Suppression of the compensatory erythropoiesis leads to prolonged postnatal anemia and an increased requirement of red blood cell transfusions after birth.

This study describes the complication rate and use of autologous and/or homologous cartilage in a large 20-year cohort of septo(rhino)plasty surgeries in a Dutch hospital, in relation to postoperative complications of septo(rhino)plasty surgery described in previous studies. A retrospective medical chart review was conducted. 2606 patients, mean age 34.7 (± 13.2) and 59.9% male, underwent primary or revision septo(rhino)plasty surgery from 01/01/1999 to 01/09/2019. Follow-up was known in 1384 of 2606 patients (53.1%) with a mean duration of 47.5 months. Complication registration was complete for 1774 patients. The overall complication rate was 270 out of 1774 (15.2%). The use of autologous costal cartilage (ACC) was a risk factor for overall complication with an odds ratio (OR) of 11.1 (95% CI 0.03-0.30; P 0.01) as compared to 5.9 (95% CI 0.06-0.45; P 0.01) when using homologous costal cartilage (HCC). Infections were more likely when ACC (5/26 [19.2%]) was used than when HCC (1/28 [3.6%]) was used. Notable resorption of cartilage was more likely when HCC (9/28 [32.1%]) was used than when ACC (1/26 [3.8%]) was used. Both the use of autologous costal cartilage grafts (OR 11.1) and homologous costal cartilage grafts (OR 5.9) lead to an increased risk of complications. When choosing cartilage type for reconstruction in septo(rhino)plasty, it should be taken into account that both ACC and HCC are associated with a higher risk of complications. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

The health risks of exposure to loud noises are a well-established fact and are widely addressed in modern industries. Yet, in less developed countries, it is thought these hazards receive less attention, both in the workplace and in private life. (1) Background: The aim of this study is to assess the occupational noise exposure in a developing country and identify possible risk groups for whom intervention is needed. (2) Methods: A cross-sectional study was performed among brewery employees in Lagos, Nigeria. Pure-tone audiometry (PTA) was performed, paired with a self-report questionnaire. Personal noise dosimetry (PND) was also performed with an additional group of participants. (3) Results: A total of 458 employees were submitted to PTA. The Packaging and Utilities department reported the largest shifts in hearing thresholds (18 dB [sd = 15] and 16 dB [sd = 15] @4kHz, respectively). No significant effect of department type on auditory health could be found. PND results were obtained from 39 employees. Packaging and Sales were identified as the most exposed departments. (4) Conclusions: A healthy hearing profile was found for a large proportion of the brewery employees (91.7%). However, NIHL (noise-induced hearing loss) proportions specifically among Bottling and Sales employees were elevated.