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Purpose: The Netherlands Longitudinal Study on Hearing (NL-SH) was set up to examine associations of hearing ability with psychosocial, work and health outcomes in working age adults., Participants: Inclusion started in 2006 and is ongoing. Currently the sample comprises 2800 adults with normal and impaired hearing, aged 18-70 years at inclusion. Five-year follow-up started in 2011, 10-year follow-up in 2016 and 15-year follow-up in 2021. All measurements are web-based. Participants perform a speech-in-noise recognition test to measure hearing ability and fill out questionnaires about their hearing status, hearing aid use, self-reported hearing disability and coping, work status and work-related outcomes (work performance, need for recovery), physical and psychosocial health (depression, anxiety, distress, somatisation, loneliness), healthcare usage, lifestyle (smoking, alcohol), and technology use., Findings to Date: The NL-SH has shown the vast implications of reduced hearing ability for the quality of life and health of working-age adults. A selection of results published in 27 papers is presented. Age-related deterioration of hearing ability accelerates after the age of 50 years. Having a history of smoking is associated with a faster decline in hearing ability, but this relationship is not found for other cardiovascular risk factors. Poorer hearing ability is associated with increased distress, somatisation, depression and loneliness. Adults with impaired hearing ability are more likely to be unemployed or unfit for work, and need more time to recuperate from work effort., Future Plans: Participant data will be linked to a national database to enable research on the association between hearing ability and mortality. Linking to environmental exposure data will facilitate insight in relations between environmental factors, hearing ability and psychosocial outcomes. The unique breadth of the NL-SH data will also allow for further research on other functional problems, for instance, hearing ability and fall risk., Trial Registration Number: NL12015.029.06., Competing Interests: Competing interests: MFvW, LAJ, TG, MS, JN, JHMvB, JRA, BIL-W, CS and SEK none. UL is affiliated with Sonova AG, one of the funding entities., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Different bacteria lead to divers diabetic foot infections (DFIs), and some bacteria probably lead to higher amputation and mortality risks. We assessed mortality and amputation risk in relation to bacterial profiles in people DFI and investigated the role of sampling method., Methods: We included people (> 18 years) with DFI in this retrospective study (2011-2020) at a Dutch tertiary care hospital. We retrieved cultures according to best sampling method: (1) bone biopsy; (2) ulcer bed biopsy; and (3) swab. We aggregated data into a composite determinant, consisting of unrepeated bacteria of one episode of infection, clustered into 5 profiles: (1) Streptococcus and Staphylococcus aureus; (2) coagulase-negative Staphylococcus, Cutibacterium, Corynebacterium and Enterococcus; (3) gram-negative; (4) Anaerobic; and (5) less common gram-positive bacteria. We calculated Hazard Ratio's (HR's) using time-dependent-Cox regression for the analyses and investigated effect modification by sampling method., Results: We included 139 people, with 447 person-years follow-up and 459 episodes of infection. Sampling method modified the association between bacterial profiles and amputation for profile 2. HR's (95% CI's) for amputation for bacterial profiles 1-5: 0.7 (0.39-1.1); stratified analysis for profile 2: bone biopsy 0.84 (0.26-2.7), ulcer bed biopsy 0.89 (0.34-2.3), swab 5.9*(2.9-11.8); 1.3 (0.78-2.1); 1.6 (0.91-2.6); 1.6 (0.58-4.5). HR's (95% CI's) for mortality for bacterial profiles 1-5: 0.89 (0.49-1.6); 0.73 (0.38-1.4); 2.6*(1.4-4.8); 1.1(0.58-2.2); 0.80(0.19-3.3)., Conclusions: In people with DFI, there was no association between bacterial profiles in ulcer bed and bone biopsies and amputation. Only in swab cultures, low-pathogenic bacteria (profile 2), were associated with a higher amputation risk. Infection with gram-negative bacteria was associated with a higher mortality risk. This study underlined the possible negative outcome of DFI treatment based on swabs cultures., (© 2022. The Author(s).)

The purpose of this study was to assess the effect of tongue-lip adhesion (TLA) on the long-term speech and articulation outcomes of patients with Robin sequence (RS) after cleft palate repair. Outcomes were compared to those in patients with RS who required positioning alone and to patients with isolated cleft palate (ICP). All consecutive patients with RS (with or without TLA) versus isolated cleft palate (ICP) who underwent cleft palate repair were retrospectively reviewed. Speech and articulation included all assessments between the age of 3-6 years. Secondary speech operations, velopharyngeal insufficiency (VPI), hypernasality, and articulation errors by cleft-type characteristics (CTC), including 4 categories (passive), non-oral, anterior-oral, and posterior-oral. A total of 41 RS patients and 61 ICP patients underwent repair with sufficient follow-up. Of them, 23 patients underwent a TLA at median age of 12 days. Rates of hypernasality (p = 0.004), secondary speech operations (p = 0.004), and posterior oral CTC (p = 0.042) were higher in RS compared to ICP. Isolated RS had speech outcomes similar to those of ICP; however, syndromic RS patients needed more secondary speech operations compared to isolated RS (p = 0.043). TLA-RS patients did not demonstrate differences in speech outcomes or any CTCs (all p > 0.05) compared to non-TLA-RS patients, except for the anterior oral CTC (74% TLA-RS vs 28% non-TLA-RS, p = 0.005). Within the limitations of the study, it seem that TLA does not affect long-term velopharyngeal function in patients with RS. However, TLA-RS patients demonstrated higher rates of anterior-oral CTC, which might be related to a different positioning of the tongue after TLA. Every effort should be taken to treat patients with RS conservatively instead of with TLA because of this demonstrated a negative effect on one type of articulation error. However, if conservative therapy fails, a TLA is still a valuable adjunct in the treatment of RS, and cleft speech pathologists who treat such patients should be more aware of this phenomenon in order to improve long-term articulation outcomes., Competing Interests: Declaration of competing interest None of the authors report any conflicts of interest. None of the authors have a financial interest in any of the products, devices, or drugs mentioned in this article., (Copyright © 2023. Published by Elsevier Ltd.)

Introduction: CD4+ T cells are thought to have a central role in the pathogenesis of autoimmune hepatitis (AIH). Mucosal addressin cell adhesion molecule-1 (MAdCAM-1) directs homing of CD4+ T cells in the alimentary tract and is a therapeutic target in inflammatory bowel diseases. Here we assessed MAdCAM-1 expression in AIH and viral hepatitis and related its expression with immune infiltrate analysis and histopathological key features., Methods: Hepatic portal areas of pretreatment biopsies (n=10) and follow-up biopsies (n=9) of patients with a confirmed diagnosis of AIH were assessed for MAdCAM-1 expression and infiltrate composition using immunohistochemistry and multispectral imaging (Vectra® Polaris™). Controls consisted of biopsies of patients with untreated chronic viral hepatitis B or C (n=22)., Results: MAdCAM-1 expression on endothelium was sparsely present in portal fields of two treatment-naïve AIH patients. Three patients showed MAdCAM-1 expression within lymphoid aggregates. No expression of significance (including single-cell expression) was observed in the remaining 6 patients. In contrast, viral hepatitis C biopsies showed endothelial MAdCAM-1 expression in 8 of 13 untreated patients. Densities of both B-cells (CD20+) and CD4+ T-cells (CD3+ CD8-) were increased in AIH and viral hepatitis patients with MAdCAM-1 expression., Conclusion: MAdCAM-1 was detected in liver biopsies in a minority of patients with AIH at the time of diagnosis suggesting no central role in its pathophysiology. Lymphoid or reticular MAdCAM-1 pattern expression was associated with more dense infiltrates of both B-cells and CD4 + T-cells, and may be related to the formation of secondary lymphoid follicles., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Background: Sexual function after hysterectomy can be a concern for patients, and research remains inconclusive about changes in sexual function associated with hysterectomy., Aim: We meta-analyzed studies on change in sexual function from pre- to posthysterectomy and the role of total vs subtotal hysterectomy and concomitant bilateral salpingo-oophorectomy (BSO) in differences in such change., Methods: We searched PubMed, Embase, and Cochrane databases from inception to January 2022. Two reviewers screened and included studies if they were published in a peer-reviewed journal and reported on sexual function pre- and posthysterectomy for benign nonprolapse indication. Methodological quality was assessed with the STROBE checklist. We used random effects multilevel models to meta-analyze standardized mean differences in pre- to postoperative sexual function and the posthysterectomy Female Sexual Function Index mean across study groups in R (RStudio)., Outcomes: Outcomes included overall sexual function, dyspareunia, desire, arousal, lubrication, and orgasm., Results: Thirty-two articles were analyzed: 8 randomized controlled trials, 20 prospective studies, 2 retrospective studies, 1 cross-sectional study, and 1 secondary analysis, comprising a total of 4054 patients. Each study provided data for at least 1 outcome. Study quality was moderate, and effect sizes showed large between-study heterogeneity. Hysterectomy was not associated with significant change in overall sexual function irrespective of surgical route, with patients tending to report potentially remaining sexual dysfunction posthysterectomy. Cervix removal was not significantly associated with differences in magnitude of change. Hysterectomy without BSO was associated with significantly stronger improvement in lubrication and orgasm than hysterectomy with BSO, which was not the case for desire, arousal or overall sexual function. However, these significant differences were not replicated within studies that directly compared cases with and without BSO., Clinical Implications: Clinicians should address remaining sexual dysfunction posthysterectomy, and BSO should not be considered if not medically required., Strengths and Limitations: We analyzed a comprehensive number of trials and studied clinically relevant factors that might relate to differences in change in sexual function. Conclusions need to be interpreted with caution since many studies showed moderate methodological quality and large effect size heterogeneity., Conclusion: Subtotal and total hysterectomy was not associated with significant change in overall sexual function irrespective of surgical route, with patients tending to report potentially remaining sexual dysfunction posthysterectomy. Hysterectomy without BSO was associated with significantly stronger improvement in lubrication and orgasm than hysterectomy with BSO. Future research on hysterectomy should analyze predictors of sexual function change trajectories, such as different indications., (© The Author(s) 2023. Published by Oxford University Press on behalf of The International Society of Sexual Medicine.)

This study aimed at investigating the change in social eating problems from diagnosis to 24 months after primary (chemo)radiotherapy and its associations with swallowing, oral function, and nutritional status, in addition to the clinical, personal, physical, psychological, social, and lifestyle dimensions. Adult patients from the NETherlands QUality of life and BIomedical Cohort (NET-QUBIC) treated with curative intent with primary (chemo)radiotherapy for newly-diagnosed HNC and who provided baseline social eating data were included. Social eating problems were measured at baseline and at 3-, 6-, 12-, and 24-month follow-up, with hypothesized associated variables at baseline and at 6 months. Associations were analyzed through linear mixed models. Included patients were 361 (male: 281 (77.8%), age: mean = 63.3, SD = 8.6). Social eating problems increased at the 3-month follow-up and decreased up to 24 months (F = 33.134, p < 0.001). The baseline-to-24 month change in social eating problems was associated with baseline swallowing-related quality of life (F = 9.906, p < 0.001) and symptoms (F = 4.173, p = 0.002), nutritional status (F = 4.692, p = 0.001), tumor site (F = 2.724, p = 0.001), age (F = 3.627, p = 0.006), and depressive symptoms (F = 5.914, p < 0.001). The 6-24-month change in social eating problems was associated with a 6-month nutritional status (F = 6.089, p = 0.002), age (F = 5.727, p = 0.004), muscle strength (F = 5.218, p = 0.006), and hearing problems (F = 5.155, p = 0.006). Results suggest monitoring social eating problems until 12-month follow-up and basing interventions on patients' features.

Myelodysplastic syndromes (MDS) comprise hematological disorders that originate from the neoplastic transformation of hematopoietic stem cells (HSCs). However, discrimination between HSCs and their neoplastic counterparts in MDS-derived bone marrows (MDS-BMs) remains challenging. We hypothesized that in MDS patients immature CD34 + CD38 - cells with aberrant expression of immunophenotypic markers reflect neoplastic stem cells and that their frequency predicts leukemic progression. We analyzed samples from 68 MDS patients and 53 controls and discriminated HSCs from immunophenotypic aberrant HSCs (IA-HSCs) expressing membrane aberrancies (CD7, CD11b, CD22, CD33, CD44, CD45RA, CD56, CD123, CD366 or CD371). One-third of the MDS-BMs (23/68) contained IA-HSCs. The presence of IA-HSCs correlated with perturbed hematopoiesis (disproportionally expanded CD34 + subsets beside cytopenias) and an increased hazard of leukemic progression (HR = 25, 95% CI: 2.9-218) that was independent of conventional risk factors. At 2 years follow-up, the sensitivity and specificity of presence of IA-HSCs for predicting leukemic progression was 83% (95% CI: 36-99%) and 71% (95% CI: 58-81%), respectively. In a selected cohort (n = 10), most MDS-BMs with IA-HSCs showed genomic complexity and high human blast counts following xenotransplantation into immunodeficient mice, contrasting MDS-BMs without IA-HSCs. This study demonstrates that the presence of IA-HSCs within MDS-BMs predicts leukemic progression, indicating the clinical potential of IA-HSCs as a prognostic biomarker., (© 2023. The Author(s).)

Background: Open inguinal hernia repair is the most commonly performed procedure in general surgery in sub-Saharan Africa, but data on its learning curve are lacking. This study evaluated the learning curve characteristics to improve surgical training and enable scaling up hernia surgery in low- and middle-income countries., Methods: Logbook data of associate clinicians enrolled in a surgical training program in Sierra Leone were collected and their first 55 hernia surgeries following the Bassini technique (herniorrhaphies) were analyzed in cohorts of five cases. Studied variables were gradient of decline of operating time, variation in operating time, and length of stay (LOS). Eleven subsequent cohorts of each five herniorrhaphies were investigated., Results: Seventy-five trainees enrolled in the training program between 2011 and 2020 were eligible for inclusion. Thirty-one (41.3%) performed the minimum of 55 herniorrhaphies, and had also complete personal logbook data. Mean operating times dropped from 79.6 (95% CI 75.3-84.0) to 48.6 (95% CI 44.3-52.9) minutes between the first and last cohort, while standard deviation in operating time nearly halved to 15.4 (95% CI 11.7-20.0) minutes, and LOS was shortened by 3 days (8.5 days, 95%CI 6.1-10.8 vs. 5.4 days, 95% 3.1-7.6). Operating times flattened after 31-35 cases which corresponded with 1.5 years of training., Conclusions: The learning curve of inguinal hernia surgery for associate clinicians flattens after 31-35 procedures. Training programs can be tailored based on this finding. The recorded learning curve may serve as a baseline for future training techniques., (© 2022. The Author(s).)

Aims/hypothesis: Both manifestations of kidney disease in diabetes, reduced eGFR (ml/min per 1.73 m 2 ) and increased urinary albumin/creatinine ratio (UACR, mg/mmol), may increase the risk of specific CVD subtypes in adults with diabetes., Methods: We assessed the prospective association between annually recorded measures of eGFR and UACR and the occurrence of myocardial infarction (MI), CHD, stroke, heart failure (HF) and cardiovascular mortality in 13,657 individuals with diabetes (53.6% male, age 62.3±12.1 years) from the Hoorn Diabetes Care System cohort, using data obtained between 1998 and 2018. Multivariate time-dependent Cox regression models adjusted for cardiovascular risk factors were used to estimate HRs and 95% CI. Associations of eGFR were adjusted for UACR values and vice versa. Effect modification by sex was investigated for all associations., Results: After a mean follow-up period of 7 years, event rates per 1000 person-years were 3.08 for MI, 3.72 for CHD, 1.12 for HF, 0.84 for stroke and 6.25 for cardiovascular mortality. Mildly reduced eGFR (60-90 ml/min per 1.73 m 2 ) and moderately to severely reduced eGFR (<59 ml/min per 1.73 m 2 ) were associated with higher risks of MI (HR 1.52; 95% CI 1.10, 2.12 and HR 1.69; 95% CI 1.09, 2.64) and CHD (HR 1.67; 95% CI 1.23, 2.26 and HR 2.01; 95% CI 1.34, 3.02) compared with normal eGFR (>90 ml/min per 1.73 m 2 ). Mildly reduced eGFR was associated with a higher risk of stroke (HR 2.53; 95% CI 1.27, 5.03). Moderately increased UACR (3-30 mg/mmol) and severely increased UACR (>30 mg/mmol) were prospectively associated with a higher cardiovascular mortality risk in men and women (HR 1.87; 95% CI 1.41, 2.47 and HR 2.78; 95% CI 1.78, 4.34) compared with normal UACR (<3 mg/mmol). Significant effect modification by sex was observed for the association between UACR and HF. Because there were a limited number of HF events within the category of UACR >30 mg/mmol, categories were combined into UACR <3.0 and >3.0 mg/mmol in the stratified analysis. Women but not men with UACR >3.0 mg/mmol had a significantly higher risk of HF compared with normal UACR (HR 2.79; 95% CI 1.47, 5.28)., Conclusions/interpretation: This study showed differential and independent prospective associations between manifestations of early kidney damage in diabetes and several CVD subtypes, suggesting that regular monitoring of both kidney function measures may help to identify individuals at higher risk of specific cardiovascular events., (© 2022. The Author(s).)

Purpose: Medulloblastoma is a rare tumor in adults. The objective of this nationwide, multicenter study was to evaluate the toxicity and efficacy of the Dutch treatment protocol for adult medulloblastoma patients., Methods: Adult medulloblastoma patients diagnosed between 2010 and 2018 were identified in the Dutch rare tumors registry or nationwide pathology database. Patients with intention to treat according to the national treatment protocol were included. Risk stratification was performed based on residual disease, histological subtype and extent of disease. All patients received postoperative radiotherapy [craniospinal axis 36 Gy/fossa posterior boost 19.8 Gy (14.4 Gy in case of metastases)]. High-risk patients received additional neoadjuvant (carboplatin-etoposide), concomitant (vincristine) and adjuvant chemotherapy (carboplatin-vincristine-cyclophosphamide) as far as feasible by toxicity. Methylation profiling, and additional next-generation sequencing in case of SHH-activated medulloblastomas, were performed., Results: Forty-seven medulloblastoma patients were identified, of whom 32 were treated according to the protocol. Clinical information and tumor material was available for 28 and 20 patients, respectively. The histological variants were mainly classic (43%) and desmoplastic medulloblastoma (36%). Sixteen patients (57%) were considered standard-risk and 60% were SHH-activated medulloblastomas. Considerable treatment reductions and delays in treatment occurred due to especially hematological and neurotoxicity. Only one high-risk patient could complete all chemotherapy courses. 5-years progression-free survival (PFS) and overall survival (OS) for standard-risk patients appeared worse than for high-risk patients (PFS 69% vs. 90%, OS 81% vs. 90% respectively), although this wasn't statistically significant., Conclusion: Combined chemo-radiotherapy is a toxic regimen for adult medulloblastoma patients that may result in improved survival., (© 2023. The Author(s).)

Background: High-grade squamous intraepithelial lesions (HSIL) or cervical intraepithelial neoplasia (CIN) grade 2/3 lesions in human papillomavirus (HPV)-positive women <30 years of age have high spontaneous regression rates. To reduce overtreatment, biomarkers are needed to delineate advanced CIN lesions that require treatment. We analyzed the FAM19A4/miR124-2 methylation test and HPV16/18 genotyping in HPV-positive women aged <30 years, aiming to identify CIN2/3 lesions in need of treatment., Methods: A European multicenter retrospective study was designed evaluating the FAM19A4/miR124-2 methylation test and HPV16/18 genotyping in cervical scrapes of 1061 HPV-positive women aged 15-29 years (690 ≤CIN1, 166 CIN2, and 205 CIN3+). A subset of 62 CIN2 and 103 CIN3 were immunohistochemically characterized by HPV E4 expression, a marker for a productive HPV infection, and p16ink4a and Ki-67, markers indicative for a transforming infection. CIN2/3 lesions with low HPV E4 expression and high p16ink4a/Ki-67 expression were considered as nonproductive, transforming CIN, compatible with advanced CIN2/3 lesions in need of treatment., Results: FAM19A4/miR124-2 methylation positivity increased significantly with CIN grade and age groups (<25, 25-29, and ≥30 years), while HPV16/18 positivity was comparable across age groups. FAM19A4/miR124-2 methylation positivity was HPV type independent. Methylation-positive CIN2/3 lesions had higher p16ink4a/Ki-67-immunoscores (P = .003) and expressed less HPV E4 (P = .033) compared with methylation-negative CIN2/3 lesions. These differences in HPV E4 and p16ink4a/Ki-67 expression were not found between HPV16/18-positive and non-16/18 HPV-positive lesions., Conclusions: Compared with HPV16/18 genotyping, the FAM19A4/miR124-2 methylation test detects nonproductive, transforming CIN2/3 lesions with high specificity in women aged <30 years, providing clinicians supportive information about the need for treatment of CIN2/3 in young HPV-positive women., Competing Interests: Potential conflicts of interest. C. J. L. M. M., R. D. M. S., and D. A. M. H. are minority shareholders of Self-screen B.V., a spin-off company of VU University Medical Center; Self-screen B.V. develops, manufactures and licences high-risk HPV and methylation marker assays for cervical cancer screening and holds patents on these tests. C. J. L. M. M. is part-time CEO of Self-screen B.V., had formerly a very small number of shares of MDXHealth and Qiagen, has received speaker fees from GlaxoSmithKline, Qiagen, and Sanofi Pasteur MSD/Merck and served occasionally on the scientific advisory boards (expert meetings) of these companies as well as Asieris Pharma/Ismar Healthcare NV (1-time payment); and received support for attending meetings and/or travel paid to author from Qiagen, GSK, SPMSD/Merck, and Self-screen B.V. J. B. is the principal investigator of studies funded in part by BD Diagnostics, Agena Bioscience, Genomica SAU, LifeRiver Biotech, and Qiagen and reports grants or contracts unrelated to this work from Capital Region of Denmark (public entity). He has received honoraria for lectures from BD Diagnostics, Roche Molecular Systems, Qiagen, and Genomica SAU. J. B. is an appointed member of the National Danish Cervical Screening Committee by the Danish Health Authority, and member of the regional cervical screening steering committee of the Capital Region of Denmark. A. O. V. has received reimbursement of travel expenses for attending conferences and honoraria for speaking from Abbott Molecular, Qiagen, and Seegene. M. d. P. has received personal fees for scientific advisory committee meetings and speaking fees from MSD and speaking fees from Roche. A. N. F. and A. T. H. are employed by Self-screen B.V., the legal manufacturer of the QIAsure Methylation Test. K. C. and R. B.’s institution has received research funding or consumables for free to support research from the following commercial entities in the last 3 years: Cepheid, Euroimmun, GeneFirst, Self-screen, Hiantis, Seegene, Roche, Abbott, and Hologic. K. C. also reports a position as advisor for nationally commissioned groups that support cervical screening in the United Kingdom (no personal payment but for work outside NHS Scotland time is reimbursed to employer). M. P. reports free-of-charge reagents and consumables received from Qiagen, Seegene, Abbott, and Roche to the author’s institution. G. G. K. reports an unpaid role as a member of the board of a patient advocacy group for gynecological cancer. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Infectious Diseases Society of America.)

Background: Compared with women who are human immunodeficiency virus (HIV) negative, women with human immunodeficiency virus (WWH) have a higher human papillomavirus (HPV) prevalence and increased cervical cancer risk, emphasizing the need for effective cervical cancer screening in this population. The present study aimed to validate methylation markers ASCL1 and LHX8 for primary screening in a South African cohort of WWH., Methods: In this post hoc analysis within the DIAgnosis in Vaccine And Cervical Cancer Screen (DiaVACCS) study, a South African observational multicenter cohort study, cervical scrape samples from 411 HIV-positive women were analyzed for hypermethylation of ASCL1 and LHX8 genes, HPV DNA, and cytology. Sensitivities, specificities, and positive and negative predictive values of primary methylation-based, HPV-based and cytology-based screening were calculated for the detection of cervical intraepithelial neoplasia of grade 3 or higher., Results: Single markers ASCL1 and LHX8 resulted in a good performance for the detection of cervical intraepithelial neoplasia of grade 3 or higher, with sensitivities of 85.9% (95% confidence interval [CI], 78.2%-93.6%) and 89.7% (83.0%-96.5%), respectively, and specificities of 72.9% (67.3%-78.5%) and 75.0% (69.5%-80.5%). Combining markers ASCL1 and LHX8 resulted in a lower sensitivity compared with HPV testing (84.6% vs 93.6%, respectively; ratio, 0.90 [95% CI, .82-.99]) and a higher specificity (86.7% vs 78.3%; ratio 1.11 [1.02-1.20]) and reduced the referral rate from 46.8% to 33.4%. ASCL1/LHX8 methylation had a significantly higher sensitivity than cytology (threshold, high-grade intraepithelial squamous lesion or worse), (84.6% vs 74.0%, respectively; ratio, 1.16 [95% CI, 1.01-1.32]) and similar specificity (86.7% vs 91.0%; ratio, 0.95 [.90-1.003])., Conclusions: Our results validate the accuracy of ASCL1/LHX8 methylation analysis for primary screening in WWH, which offers a full-molecular alternative to cytology- or HPV-based screening, without the need for additional triage testing., Competing Interests: Potential conflicts of interest. C. J. L. M. M., and R. D. M. S. are minority shareholders of Self-screen, a spin-off company of Amsterdam UMC, location Vrije Universiteit; Self-screen develops, manufactures and licenses high-risk HPV and methylation marker assays for cervical cancer screening and holds patents on these tests. A research use only version of the methylation assay has been made available by Self-screen (www.self-screen.nl). C. J. L. M. M. is the part-time chief executive officer of Self-screen and served occasionally on scientific advisory boards and/or speakers bureaus for GlaxoSmithKline (GSK), Qiagen, Sanofi Pasteur MSD/Merck, and Asieris Pharma/Ismar Healthcare. He also reports consulting fees from Qiagen, GSK, Sanofi Pasteur MSD/Merck, Asieris Pharma/Ismar Healthcare, paid to the author, and support for attending meetings and/or travel, paid to the author, from Qiagen, GSK, Sanofi Pasteur MSD/Merck, and Self-screen. He formerly had a very small number of shares of MDXHealth and Qiagen. R. D. M. S. is an inventor on patents on methylation markers for cervical cancer (patents are licensed to Self-screen). All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Aims: The aim of this study was to determine the relationship between proliferative activity, PD-L1 status and nuclear size changes after preoperative chemoradiotherapy (CRT) and the clinical outcome in patients with superior sulcus tumours., Methods: Proliferative activity (MIB-1) and PD-L1 status were estimated by immunohistochemistry in the tumour cells of resection specimen in a series of 33 patients with residual tumour after trimodality therapy for a sulcus superior tumour between 2005 and 2014. A morphometric analysis of both pretreatment and post-treatment tumour materials was also performed. Results were related to disease-free survival and overall survival., Results: Low proliferative activity (<20% MIB-1) was associated with better overall survival: 2-year overall survival of 73% compared with 43% and 25%, respectively, for moderate (MIB-1 20%-50%) and high (MIB-1 >50%) proliferative activity (p=0.016). A negative PD-L1 status (<1% positive tumour cells) was also associated with better overall survival (p=0.021). The mean nuclear size of normal lung tissue pneumocytes was significantly smaller compared with the mean nuclear size of tumour cells of the resection specimens (median difference -38.1; range -115.2 to 16.0; p<0.001). The mean nuclear size of tumour cells did not differ between pretreatment biopsies and resection specimens (median difference -4.6; range -75.2 to 86.7; p=0.14). Nuclear size was not associated with survival (p=0.82)., Conclusions: Low proliferative activity determined by MIB-1 as well as a negative PD-L1 expression are significantly associated with better overall survival in patients with residual tumour after CRT for superior sulcus tumour., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: Many partners of incurably ill cancer patients experience caregiver burden. The eHealth application "Oncokompas" supports these partners to manage their caregiver needs and to find optimal supportive care for themselves. The aim of this randomized controlled trial (RCT) was to investigate the reach of Oncokompas and its efficacy on caregiver burden, self-efficacy, and health-related quality of life (HRQOL)., Methods: The reach was estimated based on eligibility, participation rate, and an evaluation of the recruitment process. Efficacy on caregiver burden was measured using the Caregiver Strain Index + (CSI +). Secondary outcomes were self-efficacy (General Self-Efficacy Scale (GSE)) and HRQOL (EQ-5D VAS). Assessments were scheduled at baseline, 2 weeks after randomization and 3 months after baseline. Linear mixed models were used to compare longitudinal changes between the experimental and control group from baseline to the 3-month follow-up., Results: The reach, in terms of eligibility and participation rate, was estimated at 83-91%. Partners were most likely reached via palliative care consultants, patient organizations, and palliative care networks. In the one-and-a-half-year recruitment period and via the 101 organizations involved, 58 partners were included. There were no significant effects of Oncokompas on caregiver burden, self-efficacy, or HRQOL., Conclusion: The reach of Oncokompas among interested individuals was high, but the difficulties that were encountered to include partners suggest that the reach in real life may be lower. This study showed no effect of Oncokompas on caregiver burden, self-efficacy, or HRQOL in partners of incurably ill cancer patients., Relevance: The results of this study may be used in the process of developing, efficacy testing, and implementing eHealth applications for caregivers of incurably ill cancer patients., Trial Registration: Netherlands Trial Register identifier: NTR7636/NL7411. Registered on November 23, 2018 ( https://www.trialregister.nl/ )., (© 2022. The Author(s).)

Objectives: Tinnitus is highly prevalent, but only a few risk factors for developing tinnitus are known and little is known about factors associated with the degree of annoyance of new-onset tinnitus. Longitudinal analysis can reveal risk factors associated with the development of tinnitus and might lead to targeted prevention. The aim of this study is twofold. (1) To identify risk factors that are longitudinally associated with the odds of developing tinnitus 5 years later. (2) To identify factors that are cross-sectionally associated with tinnitus annoyance in adults with new-onset tinnitus., Methods: Baseline, 5-year, and 10-year follow-up data of participants in the Netherlands Longitudinal Study on Hearing (NL-SH) were used. The NL-SH is a web-based prospective cohort study, which started in 2006 and includes both normal hearing and hearing-impaired adults aged 18 to 70 years at baseline. The NL-SH uses an online digit-triplet speech-in-noise test to asses speech recognition ability in noise, and online questionnaires on various aspects of life. At follow-up, participants are asked (1) if they suffer from tinnitus and (2) to rate tinnitus annoyance on a 0 to 100 numeric rating scale. We investigated whether demographic (age, sex, living arrangement, educational level), lifestyle (history of tobacco smoking, alcohol use), health (asthma, severe heart disease, hypertension, history of stroke, osteoarthritis, rheumatoid arthritis, epilepsy, multiple sclerosis, and migraine), hearing (speech recognition ability in noise, hyperacusis, and occupational noise exposure), and psychological variables (distress, somatization, depression, and anxiety) were potential risk factors for new-onset tinnitus, or associated with annoyance caused by new-onset tinnitus. Generalized estimating equations were used to longitudinally analyze the association between potential risk factors and new-onset tinnitus measured 5 years later. A multivariable association model was constructed using a forward selection procedure with p < 0.05 for model entry. Linear regression analysis was used to cross-sectionally analyze the association between potential factors and tinnitus annoyance in new-onset tinnitus. For this purpose, a multivariable association model was constructed using a forward selection procedure with p <0.05 for model entry., Results: In total, 734 participants without tinnitus at baseline were included, from which 137 participants reported to suffer from new-onset tinnitus 5 or 10 years later. Risk factors for new-onset tinnitus were history of smoking (odds ratio 1.5, 95% confidence interval [CI] 1.0 to 2.2, p = 0.027) and higher levels of somatization (odds ratio 2.0, 95% CI 1.2 to 3.3, overall p = 0.024). Factors associated with the degree of tinnitus annoyance were increased levels of anxiety (β = 11.6, 95% CI 2.3-20.8, overall p = 0.035) and poor speech recognition ability in noise (β = 13.5, 95% CI, 4.4 to 22.6, overall p = 0.014)., Conclusions: Higher levels of somatization and a history of smoking were found to be risk factors for new-onset tinnitus 5 years later. Anxiety and poor speech recognition ability in noise were associated with higher degrees of tinnitus annoyance in new-onset tinnitus. Somatization deserves to be addressed in future research and clinical practice as it might provide part of a model for the development of chronic tinnitus., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 The Authors. Ear & Hearing is published on behalf of the American Auditory Society, by Wolters Kluwer Health, Inc.)

Longitudinal adherence to colorectal cancer (CRC) screening is reported using different summarizing measures, which hampers international comparison. We provide evidence to guide recommendations on which longitudinal adherence measure to report. Using adherence data over four stool-based CRC screening rounds in three countries, we calculated six summarizing adherence measures; adherence over all rounds, adherence per round, rescreening, full programme adherence (yes/no), regularity (never/inconsistent/consistent screenees) and number of times participated. For each measure, we calculated the accuracy in capturing the observed adherence patterns. Using the ASCCA model, we predicted screening effectiveness when using summarizing measures as model input versus the observed adherence patterns. Adherence over all rounds in the Italian, Spanish and Dutch cohorts was 64.9%, 42.8% and 61.5%, respectively, and the proportion of consistent screenees was 50.9%, 26.3% and 45.7%. Number of times participated and regularity were most accurate and resulted in similar model-predicted screening effectiveness as simulating the observed adherence patterns of Italy, Spain and the Netherlands (mortality reductions: 24.4%, 16.9% and 23.5%). Adherence over all rounds and adherence per round were least accurate. Screening effectiveness was overestimated when using adherence over all rounds (mortality reductions: 26.8%, 19.4% and 25.7%) and adherence per round (mortality reductions: 26.8%, 19.5% and 25.9%). To conclude, number of times participated and regularity were most accurate and resulted in similar model-predicted screening effectiveness as using the observed adherence patterns. However they require longitudinal data. To facilitate international comparison of CRC screening programme performance, consensus on an accurate adherence measure to report should be reached., Competing Interests: Declaration of Competing Interest Beatriz Carvalho is inventor on several biomarker patents pending. GA Meijer is co-founder and board member (CSO) of CRCbioscreen BV, he has a research collaboration with CZ Health Insurances (cash matching to ZonMW grant) and he has research collaborations with Exact Sciences, Sysmex, Sentinel Ch. SpA, Personal Genome Diagnostics (PGDX), DELFI and Hartwig Medical Foundation; these companies provide materials, equipment and/or sample/genomic analyses. Evelien Dekker has endoscopic equipment on loan of FujiFilm and Olympus, received a research grant from FujiFilm, and received honorarium for consultancy from FujiFilm, Olympus, GI Supply, CPP-FAP, PAION and Ambu, and speakers' fees from Olympus, GI Supply, Norgine, IPSEN, PAION and FujiFilm., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Personal continuity of care is a core value of general practice. It is increasingly threatened by societal and healthcare changes., Aim: To investigate the association between personal continuity and both practice and patient characteristics; and to incorporate GPs' views to enrich and validate the quantitative findings., Design and Setting: A mixed-methods study based on observational, routinely collected healthcare data from 269 478 patients from 48 Dutch general practices (2013-2018) and interviews with selected GPs., Method: First, four different personal continuity outcome measures were calculated relating to eight practice and 12 patient characteristics using multilevel linear regression analyses. Second, a thematic analysis was performed of semi-structured interviews with 10 GPs to include their views on factors contributing to personal (dis) continuity. These GPs worked at the 10 practices with the largest difference between calculated and model-estimated personal continuity., Results: Both a larger number of usual GPs working in a practice and a larger percentage of patient contacts with locum GPs were dose-dependently associated with lower personal continuity (highest versus lowest quartile -0.094 and -0.092, respectively, P <0.001), whereas days since registration with the general practice was dose-dependently associated with higher personal continuity (highest versus lowest quartile +0.017, P <0.001). Older age, number of chronic conditions, and contacts were also associated with higher personal continuity. The in-depth interviews identified three key themes affecting personal continuity: team composition, practice organisation, and the personal views of the GPs., Conclusion: Personal continuity is associated with practice and patient characteristics. The dose-dependent associations suggest a causal relationship and, complemented by GPs' views, may provide practical targets to improve personal continuity directly., (© The Authors.)

Importance: It has become common practice to offer immunocompromised patients with hematologic cancers a third COVID-19 vaccination dose, but data substantiating this are scarce., Objective: To assess whether a third mRNA-1273 vaccination is associated with increased neutralizing antibody concentrations in immunocompromised patients with hematologic cancers comparable to levels obtained in healthy individuals after the standard 2-dose mRNA-1273 vaccination schedule., Design, Setting, and Participants: This prospective observational cohort study was conducted at 4 university hospitals in the Netherlands and included 584 evaluable patients spanning the spectrum of hematologic cancers and 44 randomly selected age-matched adults without malignant or immunodeficient comorbidities., Exposures: One additional mRNA-1273 vaccination 5 months after completion of the standard 2-dose mRNA-1273 vaccination schedule., Main Outcomes and Measures: Serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens prior to and 4 weeks after a third mRNA-1273 vaccination, and antibody neutralization capacity of wild-type, Delta, and Omicron variants in a subgroup of patients., Results: In this cohort of 584 immunocompromised patients with hematologic cancers (mean [SD] age, 60 [11.2] years; 216 [37.0%] women), a third mRNA-1273 vaccination was associated with median S1-IgG concentrations comparable to concentrations obtained by healthy individuals after the 2-dose mRNA-1273 schedule. The rise in S1-IgG concentration after the third vaccination was most pronounced in patients with a recovering immune system, but potent responses were also observed in patients with persistent immunodeficiencies. Specifically, patients with myeloid cancers or multiple myeloma and recipients of autologous or allogeneic hematopoietic cell transplantation (HCT) reached median S1-IgG concentrations similar to those obtained by healthy individuals after a 2-dose schedule. Patients receiving or shortly after completing anti-CD20 therapy, CD19-directed chimeric antigen receptor T-cell therapy recipients, and patients with chronic lymphocytic leukemia receiving ibrutinib were less responsive or unresponsive to the third vaccination. In the 27 patients who received cell therapy between the second and third vaccination, S1 antibodies were preserved, but a third mRNA-1273 vaccination was not associated with significantly enhanced S1-IgG concentrations except for patients with multiple myeloma receiving autologous HCT. A third vaccination was associated with significantly improved neutralization capacity per antibody., Conclusions and Relevance: Results of this cohort study support that the primary schedule for immunocompromised patients with hematologic cancers should be supplemented with a delayed third vaccination. Patients with B-cell lymphoma and allogeneic HCT recipients need to be revaccinated after treatment or transplantation., Trial Registration: EudraCT Identifier: 2021-001072-41.

Objective: This study tested and validated an existing tool for its ability to predict the risk of long-term (ie, ≥6 weeks) sickness absence (LTSA) after four days of sick-listing., Methods: A 9-item tool is completed online on the fourth day of sick-listing. The tool was tested in a sample (N=13 597) of food retail workers who reported sick between March and May 2017. It was validated in a new sample (N=104 698) of workers (83% retail) who reported sick between January 2020 and April 2021. LTSA risk predictions were calibrated with the Hosmer-Lemeshow (H-L) test; non-significant H-L P-values indicated adequate calibration. Discrimination between workers with and without LTSA was investigated with the area (AUC) under the receiver operating characteristic (ROC) curve., Results: The data of 2203 (16%) workers in the test sample and 14 226 (13%) workers in the validation sample was available for analysis. In the test sample, the tool together with age and sex predicted LTSA (H-L test P=0.59) and discriminated between workers with and without LTSA [AUC 0.85, 95% confidence interval (CI) 0.83-0.87]. In the validation sample, LTSA risk predictions were adequate (H-L test P=0.13) and discrimination was excellent (AUC 0.91, 95% CI 0.90-0.92). The ROC curve had an optimal cut-off at a predicted 36% LTSA risk, with sensitivity 0.85 and specificity 0.83., Conclusion: The existing 9-item tool can be used to invite sick-listed retail workers with a ≥36% LTSA risk for expedited consultations. Further studies are needed to determine LTSA cut-off risks for other economic sectors.

Ultrasonography of the diaphragm in the zone of apposition has become increasingly popular to evaluate muscle thickness and thickening fraction. However, measurements in this anatomical location are frequently hindered by factors that constrain physical accessibility or that alter diaphragm position. Therefore, other anatomical positions at the chest wall for transducer placement are used, but the variability in diaphragm thickness across the dome has not been systematically studied. The aim of this study was to evaluate anatomical variation of diaphragm thickness in 46 healthy volunteers on three ventrodorsal lines and two craniocaudal positions on these three lines. The intraclass correlation coefficient (ICC) for diaphragm thickness in the craniocaudal direction on the mid-axillary line was significantly higher than those on the posterior axillary and midclavicular lines, suggesting it had the lowest variability (ICC midaxillary  = .89, 95% confidence interval [CI]: 0.83-0.93, ICC posterior axillary  = 0.74, 95% CI: 0.62-0.85, ICC midclavicular  = 0.62, 95% CI: 0.43-0.47, p < 0.05). Average diaphragm thickness was comparable on the posterior axillary and midaxillary lines and substantially larger on the midclavicular line (1.24 mm [1.06-1.47], 1.27 mm [1.10-1.42] and 2.32 [1.97-2.70], p < 0.01). We conclude that the normal diaphragm has a large variability in thickness, especially in the ventrodorsal direction. Variability in craniocaudal position is the lowest at the midaxillary line, which therefore appears to be the preferred site for diaphragm thickness measurement., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To describe the spectrum of Leber congenital amaurosis (LCA) and cone-rod dystrophy (CORD) associated with the GUCY2D gene and to identify potential end points and optimal patient selection for future therapeutic trials., Design: International, multicenter, retrospective cohort study., Subjects: Eighty-two patients with GUCY2D-associated LCA or CORD from 54 families., Methods: Medical records were reviewed for medical history, best-corrected visual acuity (BCVA), ophthalmoscopy, visual fields, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain OCT [SD-OCT], fundus autofluorescence)., Main Outcomes Measures: Age of onset, evolution of BCVA, genotype-phenotype correlations, anatomic characteristics on funduscopy, and multimodal imaging., Results: Fourteen patients with autosomal recessive LCA and 68 with autosomal dominant CORD were included. The median follow-up times were 5.2 years (interquartile range [IQR] 2.6-8.8 years) for LCA and 7.2 years (IQR 2.2-14.2 years) for CORD. Generally, LCA presented in the first year of life. The BCVA in patients with LCA ranged from no light perception to 1.00 logarithm of the minimum angle of resolution (logMAR) and remained relatively stable during follow-up. Imaging for LCA was limited but showed little to no structural degeneration. In patients with CORD, progressive vision loss started around the second decade of life. The BCVA declined annually by 0.022 logMAR (P < 0.001) with no difference between patients with the c.2513G>A and the c.2512C>T GUCY2D variants (P = 0.798). At the age of 40 years, the probability of being blind or severely visually impaired was 32%. The integrity of the ellipsoid zone (EZ) and that of the external limiting membrane (ELM) on SD-OCT correlated significantly with BCVA (Spearman ρ = 0.744, P = 0.001, and ρ = 0.712, P < 0.001, respectively) in those with CORD., Conclusions: Leber congenital amaurosis associated with GUCY2D caused severe congenital visual impairment with relatively intact macular anatomy on funduscopy and available imaging, suggesting long preservation of photoreceptors. Despite large variability, GUCY2D-associated CORD generally presented during adolescence, with a progressive loss of vision, and culminated in severe visual impairment during mid-to-late adulthood. The integrity of the ELM and EZ may be suitable structural end points for therapeutic studies of GUCY2D-associated CORD., (Copyright © 2022 American Academy of Ophthalmology. All rights reserved.)

Background: Lung cancer has the highest cancer-related mortality worldwide and earlier detection could improve outcomes. Urine circulating tumor DNA (ctDNA) represents a true non-invasive means for ambulant sample collection. In this prospective study, the potential of urine for perioperative detection of non-metastatic non-small cell lung cancer (NSCLC) using ctDNA methylation analysis is evaluated., Methods: Preoperative urine samples of 46 surgical NSCLC patients and 50 sex and age-matched controls were analyzed for DNA methylation of NSCLC-associated methylation markers CDO1, SOX17, and TAC1, using quantitative methylation-specific PCR (qMSP). The accuracy for NSCLC detection was determined by univariable and multivariable logistic regression analysis, followed by leave-one-out cross-validation. Fourteen additional urine samples were collected postoperatively to evaluate whether DNA methylation levels alter after surgery with curative intent., Results: Methylation levels of CDO1 and SOX17 were significantly elevated in patients compared to controls (P =.016 and P <.001, respectively). This marker combination yielded an area under the receiver operating curve (AUC) value of 0.71 upon leave-one-out cross-validation for non-metastatic NSCLC detection in urine. Stage I patients tended to have higher methylation levels of SOX17 as compared to stage III patients. Similar methylation levels were found across the different histological subtypes of NSCLC. In some patients with preoperative elevated methylation levels, reduced methylation levels were found in post-operative urine samples., Conclusions: Urine CDO1 and SOX17 showed increased methylation levels in NSCLC patients as compared to sex- and age-matched controls. This demonstrates that urine ctDNA methylation analysis may provide an interesting non-invasive means to detect non-metastatic NSCLC. Further studies are needed to validate the clinical usefulness of this approach and to assess the potential of post-operative monitoring., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: To analyze long-term oncological outcomes of open and percutaneous thermal ablation in the treatment of patients with colorectal liver metastases (CRLM)., Methods: This assessment from a prospective, longitudinal tumor registry included 329 patients who underwent 541 procedures for 1350 CRLM from January 2010 to February 2021. Three cohorts were formed: 2010-2013 (129 procedures [53 percutaneous]), 2014-2017 (206 procedures [121 percutaneous]) and 2018-2021 (206 procedures [135 percutaneous]). Local tumor progression-free survival (LTPFS) and overall survival (OS) data were estimated using the Kaplan-Meier method. Potential confounding factors were analyzed with uni- and multivariable Cox regression analyses., Results: LTPFS improved significantly over time for percutaneous ablations (2-year LTPFS 37.7% vs. 69.0% vs. 86.3%, respectively, P < .0001), while LTPFS for open ablations remained reasonably stable (2-year LTPFS 87.1% [2010-2013], vs. 92.7% [2014-2017] vs. 90.2% [2018-2021], P = .12). In the latter cohort (2018-2021), the open approach was no longer superior regarding LTPFS (P = .125). No differences between the three cohorts were found regarding OS (P = .088), length of hospital stay (open approach, P = .065; percutaneous approach, P = .054), and rate and severity of complications (P = .404). The rate and severity of complications favored the percutaneous approach in all three cohorts (P = .002)., Conclusion: Over the last 10 years efficacy of percutaneous ablations has improved remarkably for the treatment of CRLM. Oncological outcomes seem to have reached results following open ablation. Given its minimal invasive character and shorter length of hospital stay, whenever feasible, percutaneous procedures may be favored over an open approach., (© 2022. The Author(s).)

Objectives: To examine the effects of web-based SUpport PRogram (SUPR) for communication partners (CPs) of persons with hearing loss (PHLs) in a HA dispensing setting., Design: Cluster randomised controlled trial (cRCT) with two arms (SUPR: Booklet, online videos; care as usual: no support) plus process evaluation. Measurements: baseline, and immediately-, six, and 12 months post-intervention. Outcomes: Significant Other Scale for Hearing Disability (SOS-HEAR), International Outcome Inventory for HAs/Alternative Interventions for Significant Others (IOI-HA/AI-SO). Process evaluation: dose-received, satisfaction, and benefit., Study Sample: The cRCT included 73 (SUPR) and 57 (care as usual) CPs. In the process evaluation study, 41 CPs (SUPR) participated., Results: There were no significant effects of SUPR for third-party disability (SOS-HEAR), the proxy report (IOI-HA-SO item "use"), and third-party disability (IOI-HA-SO items "satisfaction", and "quality of life"). SUPR-videos were watched by 15-22% of the CPs. SUPR materials were rated as moderately beneficial and useful., Conclusions: Low baseline disability (floor effect) and low intervention dose-received may explain the findings. Directly targeting CPs rather than via their PHLs and providing intervention materials specifically for CPs may improve their engagement and contribute to SUPR's value supplementary to standard HA care.

Objective: Women with HIV (WWH) have an increased risk to develop recurrent cervical intraepithelial neoplasia grade 2/3 (rCIN2/3) after treatment compared with HIV-negative women. Therefore, appropriate posttreatment monitoring of WWH is important. This study evaluates the performance of ASCL1 and LHX8 methylation analysis as posttreatment monitoring test in WWH treated for CIN2/3, as alternative to cytology or human papillomavirus (HPV) as follow-up test., Design: Prospective observational cohort study., Methods: WWH treated for CIN2/3 by large loop excision of the transformation zone (LLETZ) (n  = 61) were invited for follow-up study visits at 1, 2.5 and 4 years after baseline. Baseline and follow-up cervical scrapes were tested for cytology, HPV and DNA methylation of ASCL1 and LHX8 genes. The performance of these strategies for the detection of rCIN2/3 was evaluated in the first follow-up cervical scrape., Results: Thirteen (21.3%) rCIN2/3 lesions were detected within 4 years of follow-up. In women without rCIN2/3 in follow-up, methylation levels of ASCL1 and LHX8 decreased significantly after LLETZ treatment (P  = 0.02 and 0.007, respectively). In women with rCIN2/3, methylation levels remained high after LLETZ treatment. The 4-year rCIN2/3 risk was 4.9% (95% CI: 0.6-16.5) for ASCL1/LHX8-negative women, 8.1% (95% CI: 1.7-21.9) for HPV-negative women and 7.7% (95% CI: 2.1-18.5) for cytology-negative women., Conclusion: A negative ASCL1/LHX8 methylation test in follow-up is associated with a low rCIN2/3 risk and could serve as an objective test of cure and well tolerated alternative for HPV and/or cytology screening in the posttreatment monitoring of WWH., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Dialysis is associated with frequent hospitalisations. Studies comparing hospitalisations between peritoneal dialysis (PD) and haemodialysis (HD) report conflicting results and mostly analyse data of patients that remain on their initial dialysis modality. This cohort study compares hospitalisations between PD and HD patients taking into account transitions between modalities., Methods: The Dutch nOcturnal and hoME dialysis Study To Improve Clinical Outcomes collected hospitalisation data of patients who started dialysis between 2012 and 2017. Primary outcome was hospitalisation rate, analysed with a multi-state model that attributed each hospitalisation to the current dialysis modality., Results: In total, 695 patients (252 PD, 443 HD) treated in 31 Dutch hospitals were included. The crude hospitalisation rate for PD was 2.3 ( ± 5.0) and for HD 1.4 ( ± 3.2) hospitalisations per patient-year. The adjusted hazard ratio for hospitalisation rate was 1.1 (95%CI 1.02-1.3) for PD compared with HD. The risk for first hospitalisation was 1.3 times (95%CI 1.1-1.6) higher for PD compared with HD during the first year after dialysis initiation. The number of hospitalisations and number of hospital days per patient-year were significantly higher for PD. The most common causes of PD and HD hospitalisations were peritonitis (23%) and vascular access-related problems (33%)., Conclusion: PD was associated with higher hospitalisation rate, higher risk for first hospitalisation and higher number of hospitalisations compared with HD. Since the PD hospitalisations were mainly caused by peritonitis, more attention to infection prevention is necessary for reducing the number of hospitalisations in the future., (© 2022 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Background: Results and success measures of cholesteatoma surgery are generally described using objective data whereas subjective data are mostly lacking. Patients experiences and complaints are becoming more important alongside clinical and audiometric outcome measures in cholesteatoma care., Objective: To investigate the course of patient-reported complaints, the impact of complaints, audiometric measures and the stability of audiometric measures, and complaints over time after primary and recurrent/residual cholesteatoma surgery., Methods: Postoperative patients were prospectively included and divided into primary acquired and recurrent/residual cholesteatoma. The EuroQol 5D (EQ-5D-3L), Otology Questionnaire Amsterdam (OQUA), and the Speech Spatial Questionnaire (SSQ) were completed by 144 patients up to 2 years postoperative. Patient-reported complaints divided in eight separate domains, postoperative hearing and impact on daily life were longitudinally assessed by means of linear mixed models., Results: Hearing loss and tinnitus are the most reported postoperative complaints over time. Patient-reported loss of taste and the impact of all complaints decline over time. All other patient-reported complaints remain stable over time, only itch complaints fluctuate. Primary cholesteatoma patients score significantly higher on hearing loss complaints compared with recurrent/residual patients although they have comparable mean audiometric hearing loss. Furthermore, pure-tone hearing threshold, instead of asymmetric hearing loss, is correlated with the localization domain of the SSQ., Conclusion: This study provides important insights in the course of complaints and its impact on daily life after cholesteatoma surgery. Overall, the postoperative patient-reported complaints after cholesteatoma surgery are generally low in the studied population., Competing Interests: Conflicts of Interest and Source of Funding: F.A.t.T., S.E.K., R.J.P., and P.M. were financially supported by The Netherlands Organisation for Health Research and Development (ZonMw) (grant 80-83700-9816504), Zorgverzekeraars Nederland (ZN), and Stichting Het Heinsius- Houbolt foundation. For the remaining authors none were declared., (Copyright © 2022, Otology & Neurotology, Inc.)

Purpose: To evaluate the effect of implant-based dental rehabilitation (IDR) on health-related quality of life (HRQoL) in head and neck cancer (HNC) patients after reconstruction with a free vascularized fibula flap (FFF)., Methods: Eligible patients were identified by retrospectively reviewing the medical records of patients treated in Amsterdam UMC-VUmc. HRQoL data were used from OncoQuest, a hospital-based system to collect patient-reported outcome measures in routine care. Data were used of the EORTC QLQ-C30 and QLQ-H&N 35 before FFF reconstruction (T 0 ) and after completing IDR (T 1 ). Data were statistically analysed with the chi-square test, independent samples t test and linear mixed models., Results: Out of 96 patients with maxillofacial FFF reconstruction between January 2006 and October 2017, 57 patients (19 with and 38 without IDR) had HRQoL data at T 0 and T 1 . In the cross-sectional analysis, patients with IDR scored significantly better at T 0 and T 1 on several EORTC domains compared to the patients without IDR. Weight loss was significantly different in the within-subject analysis between T 0 and T 1 for patients with IDR (p = 0.011). However, there were no significant differences in the mean changes of all the EORTC QLQ-C30 and EORTC QLQ-H&N35 scores between the defined timepoints for patients with IDR compared to those without., Conclusions: In this study, no differences were found in the course of HRQoL in HNC patients who had undergone IDR after maxillofacial FFF reconstruction, compared to those who had not. Patients should be preoperatively informed to have realistic expectations regarding the outcome of IDR., (© 2022. The Author(s).)

Purpose: Mucoepidermoid carcinoma (MEC) of the head and neck is a prevalent malignant salivary gland tumour with a reported good outcome. The aim of this study was to report the outcome in our centre., Methods: A retrospective chart analysis with survival analyses was performed combined with fluorescence in situ hybridization (FISH) analysis to assess CRTC1/3 MAML 2 fusion gene presence., Results: Sixty-four cases of MEC were identified. Median age at presentation was 51.4 years with a predominance for parotid gland involvement. Five, 10- and 20- year disease-free survival was 98%, 90% and 68%, respectively. Overall survival was 94%, 90% and 64%, respectively. Local recurrence was seen up to 14 years after primary diagnosis; distant metastases were diagnosed up to 17 years later. The overall recurrence rate was less than 20 per cent. CRTC1/3 MAML 2 fusion gene presence showed no survival benefit., Conclusion: MEC of the head and neck has a favorable outcome with the exception of high-grade MEC. PNI and nodal involvement are not rare. CRTC1/3 MAML 2 fusion gene presence showed no survival benefit. The tendency for late onset of loco-regional and distant recurrence should not be underestimated., (© 2021. The Author(s).)

Background: To investigate associations between psychological problems and the use of healthcare and informal care and total costs among head and neck cancer (HNC) patients., Method: Data were used of the NETherlands QUality of Life and Biomedical Cohort study. Anxiety and depression disorder (diagnostic interview), distress, symptoms of anxiety and depression (HADS), and fear of cancer recurrence (FCR) and cancer worry scale (CWS) were measured at baseline and at 12-month follow-up. Care use and costs (questionnaire) were measured at baseline, 3-, 6-, 12-, and 24-month follow-up. Associations between psychological problems and care use/costs were investigated using logistic and multiple regression analyses., Results: Data of 558 patients were used. Distress, symptoms of anxiety or depression, FCR, and/or anxiety disorder at baseline were significantly associated with higher use of primary care, supportive care, and/or informal care (odds ratios (ORs) between 1.55 and 4.76). Symptoms of anxiety, FCR, and/or depression disorder at 12-month follow-up were significantly associated with use of primary care, supportive care, and/or informal care (ORs between 1.74 and 6.42). Distress, symptoms of anxiety, and FCR at baseline were associated with higher total costs., Discussion: HNC patients with psychological problems make more use of healthcare and informal care and have higher costs. This is not the result of worse clinical outcomes.

Background: Many patients with incurable cancer have symptoms affecting their health-related quality of life. The eHealth application 'Oncokompas' supports patients to take an active role in managing their palliative care needs, to reduce symptoms and improve health-related quality of life (HRQOL). This randomized controlled trial was conducted to determine the efficacy of Oncokompas compared to care as usual among incurably ill cancer patients with a life expectancy of more than three months., Methods: Patients were recruited in six hospitals in the Netherlands. Eligible patients were randomly assigned to the intervention (direct access to Oncokompas) or the control group (access to Oncokompas after three months). The primary outcome measure was patient activation (i.e., patients' knowledge, skills and confidence for self-management). Secondary outcomes were general self-efficacy and HRQOL. Measures were assessed at baseline, two weeks after randomization, and three months after the baseline measurement. Linear mixed models were used to compare longitudinal changes between both groups from baseline to the three-month follow-up., Findings: In total, 219 patients were eligible of which 138 patients completed the baseline questionnaire (response rate 63%), and were randomized to the intervention (69) or control group (69). There were no significant differences between the intervention and control group over time in patient activation (estimated difference in change T0-T2; 1·8 (90% CI: -1·0 to 4·7)), neither in general self-efficacy and HRQOL. Of the patients in the intervention group who activated their account, 74% used Oncokompas as intended. The course of patient activation, general self-efficacy, and HRQOL was not significantly different between patients who used Oncokompas as intended versus those who did not., Interpretation: Among incurably ill cancer patients with a life expectancy of more than three months and recruited in the hospital setting, Oncokompas did not significantly improve patient activation, self-efficacy, or HRQOL., Funding: ZonMw, Netherlands Organization for Health Research and Development (844001105)., Competing Interests: IVdL reports grants from the Netherlands Organization for Health Research and Development (ZonMw), the Dutch Cancer Society (KWF Kankerbestrijding), Bristol Myers Squibb, Danone Ecofund/Nutricia. ABC reports grants from Roche. FdV reports grants from Foundation STOPbraintumors.org and AbbVIe, BMS, Novartis, EORTC, Vaximm and BioClin Therapeutics. FdV reports participation on a DSMB during the conduct of this study, and leaderships or fiduciary roles in other boards and commissions. All other authors declare no competing interests., (© 2022 The Author(s).)

Vaccination guidelines for patients treated for hematological diseases are typically conservative. Given their high risk for severe COVID-19, it is important to identify those patients that benefit from vaccination. We prospectively quantified serum immunoglobulin G (IgG) antibodies to spike subunit 1 (S1) antigens during and after 2-dose mRNA-1273 (Spikevax/Moderna) vaccination in hematology patients. Obtaining S1 IgG ≥ 300 binding antibody units (BAUs)/mL was considered adequate as it represents the lower level of S1 IgG concentration obtained in healthy individuals, and it correlates with potent virus neutralization. Selected patients (n = 723) were severely immunocompromised owing to their disease or treatment thereof. Nevertheless, >50% of patients obtained S1 IgG ≥ 300 BAUs/mL after 2-dose mRNA-1273. All patients with sickle cell disease or chronic myeloid leukemia obtained adequate antibody concentrations. Around 70% of patients with chronic graft-versus-host disease (cGVHD), multiple myeloma, or untreated chronic lymphocytic leukemia (CLL) obtained S1 IgG ≥ 300 BAUs/mL. Ruxolitinib or hypomethylating therapy but not high-dose chemotherapy blunted responses in myeloid malignancies. Responses in patients with lymphoma, patients with CLL on ibrutinib, and chimeric antigen receptor T-cell recipients were low. The minimal time interval after autologous hematopoietic cell transplantation (HCT) to reach adequate concentrations was <2 months for multiple myeloma, 8 months for lymphoma, and 4 to 6 months after allogeneic HCT. Serum IgG4, absolute B- and natural killer-cell number, and number of immunosuppressants predicted S1 IgG ≥ 300 BAUs/mL. Hematology patients on chemotherapy, shortly after HCT, or with cGVHD should not be precluded from vaccination. This trial was registered at Netherlands Trial Register as #NL9553., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has challenged healthcare globally. An acute increase in the number of hospitalized patients has necessitated a rigorous reorganization of hospital care, thereby creating circumstances that previously have been identified as facilitating prescribing errors (PEs), e.g. a demanding work environment, a high turnover of doctors, and prescribing beyond expertise. Hospitalized COVID-19 patients may be at risk of PEs, potentially resulting in patient harm. We determined the prevalence, severity, and risk factors for PEs in post-COVID-19 patients, hospitalized during the first wave of COVID-19 in the Netherlands, 3 months after discharge., Methods: This prospective observational cohort study recruited patients who visited a post-COVID-19 outpatient clinic of an academic hospital in the Netherlands, 3 months after COVID-19 hospitalization, between June 1 and October 1 2020. All patients with appointments were eligible for inclusion. The prevalence and severity of PEs were assessed in a multidisciplinary consensus meeting. Odds ratios (ORs) were calculated by univariate and multivariate analysis to identify independent risk factors for PEs., Results: Ninety-eight patients were included, of whom 92% had ≥1 PE and 8% experienced medication-related harm requiring an immediate change in medication therapy to prevent detoriation. Overall, 68% of all identified PEs were made during or after the COVID-19 related hospitalization. Multivariate analyses identified ICU admission (OR 6.08, 95% CI 2.16-17.09) and a medical history of COPD / asthma (OR 5.36, 95% CI 1.34-21.5) as independent risk factors for PEs., Conclusions: PEs occurred frequently during the SARS-CoV-2 pandemic. Patients admitted to an ICU during COVID-19 hospitalization or who had a medical history of COPD / asthma were at risk of PEs. These risk factors can be used to identify high-risk patients and to implement targeted interventions. Awareness of prescribing safely is crucial to prevent harm in this new patient population., (© 2022. The Author(s).)

In pediatric ophthalmology it is often necessary to obtain axial length in young children. For children older than 3 years, noncontact biometry can be used. For younger children this is usually not an option, and the clinician needs to rely on other imaging modalities. Depicted data curves in textbooks elaborate on few studies and limited number of subjects. The existing literature regarding normal axial length for preterm infants and term newborns is summarized and critically appraised for number of subjects, relevance, measurement method and error, gender and retinopathy of prematurity. We obtained axial length measurements for a total number of 6,575 eyes in 27 papers published from 1964 to 2018 (9 papers with 2,272 eyes for preterm children, 24 papers with 4,303 eyes for term children). Initially, axial length increases rapidly: from a mean 5.1-16.2 mm in week 12 to week 37 gestational age. From 38 weeks, growth rate decreases from 16.2 mm to a mean of 21.8 mm at 3 years old. Male infants have a larger average axial length than females at birth; the difference is 0.24 mm (95%CI: 0.15-0.33, P < 0.001). We present a useful growth curve and formula that may serve as a reference for diagnosing abnormal growth., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Hearing impairment may lead to an increased need to recover from fatigue and distress after a day of work. Also, hearing impairment may negatively affect the balance between workload and control over it (job demand and job control). The uptake of hearing solutions may have a positive effect on these outcomes. We aimed to assess the longitudinal relationship between change in speech recognition in noise and changes in need for recovery after work and job demand and job control, and the influence of hearing solutions on these relationships over a period of 5 years. Research questions (RQs) were as follows: (1) Is a 5-year change in speech recognition in noise associated with a change in need for recovery after work over that same 5-year period?; (2) Is a 5-year change in speech recognition in noise associated with a change in job demand and job control over that same 5-year period?; (3) What is the effect of hearing solution uptake in the 5-year period on the change in these outcomes in that same 5-year period?, Method: Data of the Netherlands Longitudinal Study on Hearing, collected between 2006 and January 2019, were divided into two 5-year follow-up intervals: T0 (baseline) to T1 (5-year follow-up) and T1 (5-year follow-up) to T2 (10-year follow-up). An online digit-triplet in noise test was used to assess speech recognition in noise. Online questionnaires on demographic, socioeconomic, and work-related characteristics were administered. For RQ1-RQ2, the study sample included adults working ≥12 hours per week, with at least two consecutive measurements (n = 783). For RQ3, employees who had not yet obtained hearing solutions at baseline, but who would be eligible based on a speech reception threshold in noise ≥ -5.5 dB signal-to-noise ratio (SNR), were included (n = 147). Longitudinal linear regression analyses using mixed models were performed to assess RQ1-RQ3., Results: After adjusting for baseline values, 5-year change in speech recognition in noise showed a statistically significant association with 5-year change in need for recovery. A worsening of 1 dB SNR in speech recognition in noise in an individual was associated with an increase of 0.72 units in need for recovery (scale range 0 to 100). A 5-year change in speech recognition in noise was not significantly associated with a 5-year change in job demand or job control. The uptake of hearing solutions in the 5-year period did not have a significant effect on change in need for recovery in that same 5-year period., Conclusion: The significant longitudinal association between 5-year worsening in speech recognition in noise and increase in need for recovery over the same time period strengthens the evidence for the importance of early detection of a worsening in speech recognition in noise to identify employees with an increase in need for recovery. The absence of an effect of the uptake of a hearing solution on need for recovery indicates that additional alternative interventions may be needed to foster beneficial use of hearing solutions as well as to mitigate the increased need for recovery in case of worsening speech recognition in noise., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We aimed to assess whether longer indwelling time of peripherally inserted central catheters (PICC) increases risk of central line associated bloodstream infections (CLABSI) in haematology patients., Methods: Multicentre retrospective cohort study among haematology patients receiving PICCs between 2013 and 2015. Occurrence of CLABSI based on CDC definitions was assessed. We calculated incidence rates, determined risk factors for CLABSI and used Poisson regression models to assess the risk of developing CLABSI as a function of PICC dwell time. We compared diagnoses and treatment characteristics between 2013-2015 and 2015-2020., Results: 455 PICCs placed in 370 patients were included, comprising 19,063 catheter days. Median indwelling time was 26 days (range 0-385) and CLABSI incidence was 4.0 per 1000 catheter days, with a median time to CLABSI of 33 days (range 18-158). Aplastic anaemia (AA) was associated with an increased risk of CLABSI; patients undergoing autologous stem cell transplantation (SCT) were less likely to develop CLABSI. In the unadjusted analysis, PICCs with an indwelling time of 15-28 days, 29-42 days, 43-56 days and > 56 days each had an increased CLABSI incidence rate ratio of 2.4 (1.2-4.8), 2.2 (0.95-5.0), 3.4 (1.6-7.5) and 1.7 (0.9-3.5), respectively, compared to PICCs in place for < 15 days. However, after adjusting for AA and SCT, there was no significant difference in incidence rates between dwell times (p 0.067)., Conclusions: Our study shows that risk of CLABSI does not appear to increase with longer PICC indwelling time. Routine replacement of PICCs therefore is unlikely to prevent CLABSI in this population., (© 2022. The Author(s).)

Background: The development of accurate urinary biomarkers for non-invasive and cost-effective detection of primary and recurrent bladder tumours is recognized as one of the major clinical needs in bladder cancer diagnostics. The purposes of this study were (1) to validate the results of a previous technical comparison by determining the diagnostic performance of nine methylation markers in urine pellet compared to full void urine, and (2) to validate the diagnostic performance of the optimal marker panel GHSR/MAL from a previous exploratory study in a preclinical setting., Methods: Urine samples of 108 patients with bladder cancer and 100 age- and gender-matched controls were prospectively collected for methylation analysis. Urinary methylation levels of the markers FAM19A4, GHSR, MAL, miR-129, miR-935, PHACTR3, PRDM14, SST and ZIC1 were determined with quantitative methylation-specific PCR in urine pellet. Area under the curves (AUCs) were determined for individual markers and the marker panel GHSR/MAL. The diagnostic performance of the marker panel GHSR/MAL was evaluated in the total study population and in different subgroups of patients with bladder cancer using the Chi-square test. The diagnostic accuracy was assessed by leave-one-out cross-validation., Results: All nine urinary methylation markers (FAM19A4, GHSR, MAL, miR-129, miR-935, PHACTR3, PRDM14, SST and ZIC1) showed significantly higher methylation levels in bladder cancer patients than in controls (p < 0.001). Area under the curves (AUCs) of the nine methylation markers tested in urine pellet were similar to AUCs in full void urine of an independent previous cohort. GHSR/MAL reached an AUC of 0.89 (95% confidence interval [CI] 0.84-0.94), at 80% sensitivity and 93% specificity. Sensitivity of GHSR/MAL increased with higher tumour grades, higher tumour stages, in primary vs. recurrent tumours, and in males vs. females., Conclusions: This technical validation supports the robustness of DNA methylation analysis in urine pellet and full void urine for the non-invasive detection of bladder cancer. Subsequent preclinical validation confirmed the diagnostic potential of GHSR/MAL. These findings underline the diagnostic potential of the marker panel GHSR/MAL for future bladder cancer diagnostics., (© 2022. The Author(s).)

Background: The introduction of primary HPV screening has doubled the number of colposcopy referrals because of the direct referral of HPV-positive women with a borderline or mild dyskaryosis (BMD) cytology (ASC-US/LSIL) triage test. Further risk-stratification is warranted to improve the efficiency of HPV-based screening., Methods: This study evaluated the discriminative power of FAM19A4/miR124-2 methylation, HPV16/18 genotyping and HPV16/18/31/33/45 genotyping in HPV-positive women with BMD (n = 294) in two Dutch screening trials. Absolute CIN3+ risks and colposcopy referrals within one screening round were calculated., Results: Methylation analysis discriminated well, yielding a CIN3+ risk of 33.1% after a positive result and a CIN3+ risk of 9.8% after a negative result. HPV16/18 and HPV16/18/31/33/45 genotyping resulted in a 27.6% and 24.6% CIN3+ risk after a positive result, and a 13.2% and 9.1% CIN3+ risk after a negative result. Colposcopy referral percentages were 41.2%, 43.2%, and 66.3% for FAM19A4/miR124-2 methylation, HPV16/18 and HPV16/18/31/33/45 genotyping, respectively. The CIN3+ risk after a negative result could be lowered to 2.8% by combining methylation and extended genotyping, at the expense of a higher referral percentage of 75.5%., Conclusion: The use of FAM19A4/miR124-2 methylation and/or HPV genotyping in HPV-positive women with BMD can lead to a substantial reduction in the number of direct colposcopy referrals., (© 2021. The Author(s).)

Purpose: To describe the natural course, phenotype, and genotype of patients with X-linked retinoschisis (XLRS)., Design: Retrospective cohort study., Participants: Three hundred forty patients with XLRS from 178 presumably unrelated families., Methods: This multicenter, retrospective cohort study reviewed medical records of patients with XLRS for medical history, symptoms, visual acuity (VA), ophthalmoscopy, full-field electroretinography, and retinal imaging (fundus photography, spectral-domain [SD] OCT, fundus autofluorescence)., Main Outcome Measures: Age at onset, age at diagnosis, severity of visual impairment, annual visual decline, and electroretinography and imaging findings., Results: Three hundred forty patients were included with a mean follow-up time of 13.2 years (range, 0.1-50.1 years). The median ages to reach mild visual impairment and low vision were 12 and 25 years, respectively. Severe visual impairment and blindness were observed predominantly in patients older than 40 years, with a predicted prevalence of 35% and 25%, respectively, at 60 years of age. The VA increased slightly during the first 2 decades of life and subsequently transitioned into an average annual decline of 0.44% (P < 0.001). No significant difference was found in decline of VA between variants that were predicted to be severe and mild (P = 0.239). The integrity of the ellipsoid zone (EZ) as well as the photoreceptor outer segment (PROS) length in the fovea on SD OCT correlated significantly with VA (Spearman's ρ = -0.759 [P < 0.001] and -0.592 [P = 0.012], respectively). Fifty-three different RS1 variants were found. The most common variants were the founder variant c.214G→A (p.(Glu72Lys)) (101 patients [38.7%]) and a deletion of exon 3 (38 patients [14.6%])., Conclusions: Large variabilities in phenotype and natural course of XLRS were seen in this study. In most patients, XLRS showed a slow deterioration starting in the second decade of life, suggesting an optimal window of opportunity for treatment within the first 3 decades of life. The integrity of EZ as well as the PROS length on SD OCT may be important in choosing optimal candidates for treatment and as potential structural end points in future therapeutic studies. No clear genotype-phenotype correlation was found., (Copyright © 2021 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

Background: eHealth and social media could be of particular benefit to adults with hearing impairment, but it is unknown whether their use of smart devices, apps, and social media is similar to that of the general population., Objective: Our aim is to study whether adults with normal hearing and those with impaired hearing differ in their weekly use of smart devices, apps, and social media; reasons for using social media; and benefits from using social media., Methods: We used data from a Dutch cohort, the National Longitudinal Study on Hearing. Data were collected from September 2016 to April 2020 using a web-based questionnaire and speech-in-noise test. The results from this test were used to categorize normal hearing and hearing impairment. Outcomes were compared using (multiple) logistic regression models., Results: Adults with impaired hearing (n=384) did not differ from normal hearing adults (n=341) in their use of a smartphone or tablet. They were less likely to make use of social media apps on a smartphone, tablet, or smartwatch (age-adjusted odds ratio [OR] 0.67, 95% CI 0.48-0.92; P=.02). Use of social media on all devices and use of other apps did not differ. Adults with hearing impairment were more likely to agree with using social media to stay in touch with family members (OR 1.54, 95% CI 1.16-2.07; P=.003) and friends (age-adjusted OR 1.35, 95% CI 1.01-1.81; P=.046). Furthermore, they were more likely to agree with using social media to perform their work (age-adjusted OR 1.51, 95% CI 1.04-2.18; P=.03). There were no differences in the experienced benefits from social media., Conclusions: The potential for eHealth is confirmed because adults with hearing impairment are not less likely to use smart devices than their normal hearing peers. Adults with hearing impairment are less likely to use social media apps on a smart device but not less likely to use social media on all types of internet-connected devices. This warrants further research on the types of social media platforms that adults with hearing impairment use and on the type of device on which they prefer to use social media. Given that participants with hearing impairment are more likely than their normal hearing peers to use social media to perform their work, use of social media may be seen as an opportunity to enhance vocational rehabilitation services for persons with hearing impairment., (©Marieke F van Wier, Emily Urry, Birgit I Lissenberg-Witte, Sophia E Kramer. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 20.12.2021.)

There is currently no consensus regarding preferred clinical outcome measures following image-guided tumor ablation or clear definitions of oncologic end points. This consensus document proposes standardized definitions for a broad range of oncologic outcome measures with recommendations on how to uniformly document, analyze, and report outcomes. The initiative was coordinated by the Society of Interventional Oncology in collaboration with the Definition for the Assessment of Time-to-Event End Points in Cancer Trials, or DATECAN, group. According to predefined criteria, based on experience with clinical trials, an international panel of 62 experts convened. Recommendations were developed using the validated three-step modified Delphi consensus method. Consensus was reached on when to assess outcomes per patient, per session, or per tumor; on starting and ending time and survival time definitions; and on time-to-event end points. Although no consensus was reached on the preferred classification system to report complications, quality of life, and health economics issues, the panel did agree on using the most recent version of a validated patient-reported outcome questionnaire. This article provides a framework of key opinion leader recommendations with the intent to facilitate a clear interpretation of results and standardize worldwide communication. Widespread adoption will improve reproducibility, allow for accurate comparisons, and avoid misinterpretations in the field of interventional oncology research. Published under a CC BY 4.0 license. Online supplemental material is available for this article. See also the editorial by Liddell in this issue.

Concurrent chemoradiotherapy (cCRT) is the preferred treatment for stage III NSCLC because surgery containing multimodality treatment is often not appropriate. Alternatives, often for less fit patients, include sequential CRT and RT alone. Many reports describing the relationship between overall survival (OS), toxicity, and dosimetry are based on clinical trials, with strict criteria for patient selection. We performed an institutional analysis to study the relationship between dosimetric parameters, toxicity, and OS in inoperable patients with stage III NSCLC treated with (hybrid) IMRT/VMAT-based techniques in routine clinical practice. Eligible patients had undergone treatment with radical intent using cCRT, sCRT, or RT alone, planned to a total dose ≥ 50 Gy delivered in ≥15 fractions. All analyses were performed for two patient groups, (1) cCRT ( n = 64) and (2) sCRT/RT ( n = 65). The toxicity rate differences between the two groups were not significant, and OS was 29 and 17 months, respectively. For sCRT/RT, no dosimetric factors were associated with OS, whereas for cCRT, PTV-volume, esophagus V50 Gy, and contralateral lung V5 Gy were associated. cCRT OS was significantly lower in patients with esophagitis ≥ G2. The overall rate of ≥G3 pneumonitis was low (3%), and the rate of high-grade esophagitis the OS in this real-world patient population was comparable to those reported in clinical trials. Based on this hypothesis-generating data, more aggressive esophageal sparing merits consideration. Institutional auditing and benchmarking of the planning strategy, dosimetry, and outcome have an important role to play in the continuous quality improvement process.

Objectives: To evaluate the process of implementing a web-based support program (SUPR) for hearing aid users in the Dutch dispensing setting in order to allow interpretation of the randomized controlled trial's results (positive effects on hearing-aid related outcomes; no effects on psychosocial outcomes). Design: Measures: context of implementation, recruitment, SUPR's: reach, implementation fidelity, dose delivered, dose received, satisfaction, and benefit. Data collection: quantitative and qualitative. Study Sample: One hundred thirty-eight clients (mean age 68.1 years; 60% male) and 44 dispensers completed questionnaires. Five clients and 6 dispensers participated in interviews and focus groups. Results: Clients and dispensers were generally satisfied with SUPR's usefulness. SUPR-videos were watched by 7-37% of the clients. Around half of the dispensers encouraged clients to watch them or informed them about SUPR. Some clients found the SUPR-materials suboptimal, and changes in personnel and limited dispenser-training were barriers acting on a contextual level. Conclusions: This study identified several factors that contributed to the success of SUPR. Others factors, acting on various levels (e.g., intervention material, dispensers, and implementation context), were suboptimal and may explain the absent psychosocial effects. The identified factors are important to consider in further development of SUPR, and in other web-based support programs., Competing Interests: Most of JM's appointment at the Amsterdam UMC as a PhD student on the SUPR project (including carrying out the tasks related to the submitted work), and the design and implementation of the SUPR study were facilitated through a research grant sponsored by Audionova International. MP was employed as a researcher at Schoonenberg HoorSupport (daughter company of Audionova International) for a 6-month period on other research work, received a (co-funding) research grant from Sonova AG (mother company of Audionova International) for other research work, and has been paid for delivering a one-off scientific presentation for Sonova AG. VJ is an employee at Schoonenberg HoorSupport. SK has been paid for delivering a presentation for Sonova AG; no other relationships or activities that could appear to have influenced the submitted work can be reported. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Meijerink, Pronk, Lissenberg-Witte, Jansen and Kramer.)

This cohort study aimed to evaluate efficacy, safety, and survival outcomes of neoadjuvant chemotherapy (NAC) followed by repeat local treatment compared to upfront repeat local treatment of recurrent colorectal liver metastases (CRLM). A total of 152 patients with 267 tumors from the prospective Amsterdam Colorectal Liver Met Registry (AmCORE) met the inclusion criteria. Two cohorts of patients with recurrent CRLM were compared: patients who received chemotherapy prior to repeat local treatment (32 patients) versus upfront repeat local treatment (120 patients). Data from May 2002 to December 2020 were collected. Results on the primary endpoint overall survival (OS) and secondary endpoints local tumor progression-free survival (LTPFS) and distant progression-free survival (DPFS) were reviewed using the Kaplan-Meier method. Subsequently, uni- and multivariable Cox proportional hazard regression models, accounting for potential confounders, were estimated. Additionally, subgroup analyses, according to patient, initial and repeat local treatment characteristics, were conducted. Procedure-related complications and length of hospital stay were compared using chi-square test and Fisher's exact test. The 1-, 3-, and 5-year OS from date of diagnosis of recurrent disease was 98.6%, 72.5%, and 47.7% for both cohorts combined. The crude survival analysis did not reveal a significant difference in OS between the two cohorts ( p = 0.834), with 1-, 3-, and 5-year OS of 100.0%, 73.2%, and 57.5% for the NAC group and 98.2%, 72.3%, and 45.3% for the upfront repeat local treatment group, respectively. After adjusting for two confounders, comorbidities ( p = 0.010) and primary tumor location ( p = 0.023), the corrected HR in multivariable analysis was 0.839 (95% CI, 0.416-1.691; p = 0.624). No differences between the two cohorts were found with regards to LTPFS (HR = 0.662; 95% CI, 0.249-1.756; p = 0.407) and DPFS (HR = 0.798; 95% CI, 0.483-1.318; p = 0.378). No heterogeneous treatment effects were detected in subgroup analyses according to patient, disease, and treatment characteristics. No significant difference was found in periprocedural complications ( p = 0.843) and median length of hospital stay ( p = 0.600) between the two cohorts. Chemotherapy-related toxicity was reported in 46.7% of patients. Adding NAC prior to repeat local treatment did not improve OS, LTPFS, or DPFS, nor did it affect periprocedural morbidity or length of hospital stay. The results of this comparative assessment do not substantiate the routine use of NAC prior to repeat local treatment of CRLM. Because the exact role of NAC (in different subgroups) remains inconclusive, we are currently designing a phase III randomized controlled trial (RCT), COLLISION RELAPSE trial, directly comparing upfront repeat local treatment (control) to neoadjuvant systemic therapy followed by repeat local treatment (intervention).

Middle ear adenomatous neuroendocrine tumours (MEANTs) are rare, unpredictable tumours. Although most MEANTs are characterized by a benign biological behaviour and indolent growth pattern, some studies have reported locally invasive and metastastic disease. Currently, the optimal management strategy for MEANTs remains subject of debate. The aim of this study is to review the literature on MEANTs with focus on its clinical characteristics, treatment strategies and outcome. A systematic review was conducted using PubMed, Embase and Cochrane databases. A total of 111 studies comprising 198 patients with MEANT were included. Treatment modalities comprised surgery (90%), surgery with adjuvant radiotherapy (9%) and palliative (chemo)radiotherapy in (1%). Local recurrence was observed in 25% of the patients and 7% of the patients developed metastasis, over a median period of 5.7 years (range 7 months - 32 years). Twelve of 13 patients (92%) who developed metastases had a local recurrence. Four patients (2%) died of MEANT: three due to distant metastases and one due to extensive local recurrence. Reliable histopathologic predictors of outcome could not be identified. These findings indicate that the clinical presentations of MEANT vary substantially, the overall recurrence rate is considerable and initial local tumour control is paramount. Because of the unpredictable clinical course, prolonged follow-up is warranted., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose: The aim of this pretest-posttest study was to investigate the reach and effects of My Changed Body (MyCB), an expressive writing activity based on self-compassion, among head and neck cancer (HNC) survivors., Methods: This pilot study had a pretest-posttest design. HNC survivors received an invitation to complete a baseline survey on body image-related distress. At the end of the survey, HNC survivors were asked if they were interested in the intervention study. This entailed the writing activity and a survey 1 week and 1 month post-intervention. The reach was calculated by dividing the number of participants in the intervention study, by the number of (1) eligible HNC survivors and (2) those who filled in the baseline survey. Linear mixed models were used to analyze the effect on body image-related distress. Logistic regression analysis was used to investigate factors associated with the reach and reduced body image-related distress. MyCB was evaluated using study-specific questions., Results: The reach of MyCB was 15-33% (depending on reference group) and was associated with lower education level, more social eating problems, and fewer wound healing problems. Among the 87 participants, 9 (10%) showed a clinically relevant improvement in body image-related distress. No significant effect on body image-related distress was found. Self-compassion improved significantly during follow-up until 1 month post-intervention (p=0.003). Users rated satisfaction with MyCB as 7.2/10., Conclusion: MyCB does not significantly improve body image-related distress, but is likely to increase self-compassion, which sustains for at least 1 month., (© 2021. The Author(s).)

Introduction: Tactile and erogenous sensitivity of the neophallus after phalloplasty is assumed to affect the sexual well-being of transmasculine persons and, ultimately, their quality of life. The experienced and objective sensation of the neophallus and their association are largely unknown., Aim: This study evaluated experienced tactile and erotic sensation of the neophallus in transmasculine persons and investigated how this was related to objective tactile sensitivity., Methods: Between August 2017 and January 2020, 59 transmasculine persons who underwent phalloplasty were recruited to participate in a prospective follow-up study. Tactile sensitivity of the neophallus and donor-site was measured (Semmes-Weinstein Monofilament test) and compared, and participants were asked to fill out a questionnaire about experienced sensation of the neophallus and sexual wellbeing., Main Outcome Measures: Experienced and objective sensation of the neophallus were measured by using a questionnaire and Semmes-Weinstein Monofilament scores., Results: Neophallic tactile sensitivity was significantly reduced compared to the donor-site (n = 44), with the proximal part being more sensitive than the distal part (median follow-up of 1.8 years, range 1.0-7.2)). Sensitivity of the neophallus was not significantly associated with the surgical flap used, yet increased significantly with follow-up time. The questionnaire was completed by 26 participants of which 24 (92.3%) experienced (some degree of) tactile sensitivity in their neophallus. Erogenous sensation was experienced by 23 (88.5%). Experienced and objectified tactile sensitivity were not significantly correlated (Spearmans's rho = 0.23, P = .26). Answers to open-ended questions showed that results often do not match expectations., Conclusion: Tactile sensation of the neophallus was reduced in most transmasculine persons and improved slowly over time. A significant association between subjective and objective measures could not be detected. Although experienced sensitivity varied between individuals, the vast majority reported to have tactile and erotic sensitivity in the neophallus.Transmasculine persons should be informed that sensitivity of the neophallus will likely be reduced. Elfering L, van de Grift TC, Al-Tamimi M, et al. How Sensitive Is the Neophallus? Postphalloplasty Experienced and Objective Sensitivity in Transmasculine Persons. Sex Med 2021;9:100413., (Copyright © 2021 International Society for Sexual Medicine. Published by Elsevier Inc. All rights reserved.)