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Although cystoscopy is a reliable tool for detecting bladder cancer (BC) in patients with hematuria, it is invasive, costly and often unnecessary since most patients with hematuria do not have BC. Consequently, developing urinary biomarkers for non-invasive BC detection is a major clinical need. While DNA methylation markers hold promise, diagnostic performance can still be improved. We assessed 11 candidate methylation markers for urinary BC detection. Urine samples from 77 primary BC patients and 69 controls were used for marker selection and training, with independent validation conducted on samples from 63 primary BC patients and 71 controls. Samples were self-collected at home, mailed to the hospital and analyzed via quantitative methylation-specific polymerase chain reaction. Marker performance was evaluated through univariable and multivariable logistic regression analyses. Decision curve analysis (DCA) gauged clinical utility by potential cystoscopy reduction. Evaluation identified three most promising markers: NRN1, GALR1, and HAND2. These markers exhibited significantly elevated methylation levels in BC compared to controls in both cohorts (P < 0.001). The combined marker set demonstrated an area under the curve (AUC) of 0.94 at 84% (95% CI: 76-92%) sensitivity and 96% (95% CI: 91-100%) specificity. Validation yielded nearly equivalent accuracy (AUC 0.89, sensitivity 76% (95% CI: 65-86%), specificity 93% (95% CI: 86-99%)). DCA indicated a potential of 20 to 35% reduction in cystoscopies depending on the clinical scenario. The excellent diagnostic potential of our methylation markers for non-invasive BC detection, emphasizes their significance for future diagnostic strategies., Competing Interests: Declarations. Competing interests: Renske D. M. Steenbergen holds a minority stake in Self-screen B.V., a spin-off company of Amsterdam UMC, location VUmc, which owns patents and products related to the development of methylation markers for cervical screening. All other authors do not have any competing interest to declare. Ethics approval and consent to participate: The study was conducted in accordance with the Declaration of Helsinki. The study protocol was approved by the Medical Ethics Committee (2018.355 [16-10-2018], WO 18.155 [21-12-2018]) and all participants provided informed written consent before inclusion in the study., (© 2024. The Author(s).)

Background: Evaluating a patient's medication list is critical to reduce prescribing errors (PEs), but is a labour- and time-intensive process. Identification of patients at risk of PEs could improve the allocation of scarce time and resources, but currently available prediction tools are not effective., Objective: To investigate whether ward doctors can identify patients at risk of PEs., Methods: This prospective matched case-control study was conducted on three clinical wards in an academic hospital. Otolaryngology and oncology ward doctors used clinical intuition to select patients requiring a clinical medication review (CMR) (cases). These patients were then matched 1:1 on age (±10 years) and number (±1) of prescriptions with patients not selected for CMRs on the internal medicine and upper gastrointestinal surgery ward (controls). A multidisciplinary in-hospital pharmacotherapeutic stewardship team assessed the prevalence of PEs., Results: A total of 387 patients with 5191 prescriptions were included. Overall, 799 PEs affecting 279 patients (72.1%) were identified. Most PEs (58.8%) occurred during hospitalization. There were no significant differences in age, number of prescriptions, sex, renal function or documented allergies or intolerances between the cases and controls or between controls and other patients who did not receive a CMR. The incidence of PEs was higher in cases than in controls (97.5% vs 72.5%, odds ratio = 14.8, 95% confidence interval [CI] 1.8-121.1, P = .002)). The rate of PEs was three times higher in cases than in controls (incidence rate ratio = 3.0, 95% CI 2.3-4.0, P < .001)., Conclusions: Ward doctors can effectively identify patients with PEs, and thus at risk of medication-related harm, using clinical intuition., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Potentially curative therapy for locally advanced gastric cancer consists of gastrectomy, usually in combination with perioperative chemotherapy. An oncological resection includes a radical (R0) gastrectomy and modified D2 lymphadenectomy; generally, a total omentectomy is also performed, to ensure the removal of possible microscopic disease. However, the omentum functions as a regulator of regional immune responses to prevent infections and prevents adhesions which could lead to bowel obstructions. Evidence supporting a survival benefit of routine complete omentectomy during gastrectomy is lacking., Methods: OMEGA is a randomized controlled, open, parallel, non-inferiority, multicenter trial. Eligible patients are operable (ASA < 4) and have resectable (≦ cT4aN3bM0) primary gastric cancer. Patients will be 1:1 randomized between (sub)total gastrectomy with omentum preservation distal of the gastroepiploic vessels versus complete omentectomy. For a power of 80%, the target sample size is 654 patients. The primary objective is to investigate whether omentum preservation in gastrectomy for cancer is non-inferior to complete omentectomy in terms of 3-year overall survival. Secondary endpoints include intra- and postoperative outcomes, such as blood loss, operative time, hospital stay, readmission rate, quality of life, disease-free survival, and cost-effectiveness., Discussion: The OMEGA trial investigates if omentum preservation during gastrectomy for gastric cancer is non-inferior to complete omentectomy in terms of 3-year overall survival, with non-inferiority being determined based on results from both the intention-to-treat and the per-protocol analyses. The OMEGA trial will elucidate whether routine complete omentectomy could be omitted, potentially reducing overtreatment., Trial Registration: ClinicalTrials.gov NCT05180864. Registered on 6 th January 2022., (© 2024. The Author(s).)

Objective: To determine whether intercurrent infections are a risk factor for subsequent disease flares in systemic lupus erythematosus (SLE)., Methods: Demographic and clinical characteristics of 203 patients with SLE participating in the Amsterdam SLE cohort were collected at baseline and during follow-up. Collection of data on infections and SLE flares was registry-based and infections and flares were categorised as minor or major, based on predefined criteria. Proportional hazard models with recurrent events and time-varying covariates were used to estimate the HR of SLE flares., Results: The incidence rates of major and minor infections were 5.3 per 100 patient years and 63.9 per 100 patient years, respectively. The incidence rates of flares were 3.6 and 15.1 per 100 patient years for major flares and minor flares, respectively.In the proportional hazard model, intercurrent infections (major and minor combined) were associated with the occurrence of SLE flares (major and minor combined; HR 1.9, 95% CI: 1.3 to 2.9). The hazard ratio for a major SLE flare following a major infection was 7.4 (95% CI: 2.2 to 24.6). Major infections were not associated with the occurrence of minor flares., Conclusions: The results of the present study show that intercurrent infections are associated with subsequent SLE flares, which supports the hypothesis that infections may trigger SLE flares., Competing Interests: Competing interests: IEMB reports personal fees from GSK, Eli Lilly, UCB, Roche, Sanofi Genzyme and AstraZeneca, outside the submitted work. FeH, MWPT-A-S, BIL-W and AEV have no conflicts of interest to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The simultaneous presence of colorectal liver metastases (CRLMs) and extrahepatic metastases in patients with colorectal cancer (CRC) can be considered a relative contraindication for local treatment with curative intent. This study aims to assess the survival outcomes of patients with CRLMs and extrahepatic metastases after comprehensive local treatment of all metastatic sites., Methods: Patients with CRLMs who received local treatment of all metastatic sites were extracted from the prospective AmCORE registry database and subdivided into two groups: CRLM only vs. CRLM and extrahepatic metastasis. To address potential confounders, multivariate analysis was performed. The primary endpoint was overall survival (OS)., Results: In total, 881 patients with CRLM only and 60 with CRLM and extrahepatic disease were included, and the median OS was 55.7 months vs. 42.7 months, respectively. Though OS was significantly lower in patients with concomitant extrahepatic metastases (HR 1.477; 95% CI 1.029-2.121; p = 0.033), the survival curve plateaued after 6.2 years. Extrahepatic manifestations were pulmonary (43.3%), peritoneal (16.7%) and non-regional lymph node metastases (10.0%). In patients with pulmonary and non-regional lymph node metastases, OS did not significantly differ from patients with CRLM-only disease; concomitant peritoneal metastases showed an inferior OS (HR 1.976; 95% CI 1.017-3.841, p = 0.041)., Conclusions: In this comparative series, OS was inferior for patients with multi-organ metastatic CRC versus patients with CRLMs alone. Nonetheless, the long-term survival curve plateau seemed to justify local treatment in a subset of patients with multi-organ metastatic CRC, especially for patients with CRLMs and pulmonary or lymph node metastases.

Background: This study examined the relationship between speech-in-noise recognition and incident/recurrent falls due to balance problems ten years later (RQ-1); 10-year change in speech-in-noise recognition and falls (RQ-2a), as well as the role of dizziness in this relationship (RQ-2b). The association between hearing aid use and falls was also examined (RQ-3)., Methods: Data was collected from the Netherlands Longitudinal Study on Hearing between 2006 and December 2022. Participants completed an online survey and digits-in-noise test every five years. For this study, data was divided into two 10-year follow-up time intervals: T0 (baseline) to T2 (10-year follow-up), and T1 (5-years) to T3 (15-years). For all RQs, participants aged ≥ 40 years at baseline, without congenital hearing loss, and non-CI users were eligible (n = 592). Additionally, for RQ-3 participants with a speech reception threshold in noise (SRTn) ≥ -5.5 dB signal-to-noise ratio were included (n = 422). Analyses used survey variables on hearing, dizziness, falls due to balance problems, chronic health conditions, and psychosocial health. Logistic regressions using General Estimating Equations were conducted to assess all RQs., Results: Among individuals with obesity, those with poor baseline SRTn had a higher odds of incident falls ten years later (odds ratio (OR):14.7, 95% confidence interval (CI) [2.12, 103]). A 10-year worsening of SRTn was significantly associated with a higher odds of recurrent (OR: 2.20, 95% CI [1.03, 4.71]) but not incident falls. No interaction was found between dizziness and change in SRTn. Hearing aid use (no use/ < 2 years use vs. ≥ 2 years) was not significantly associated with incident nor recurrent falls. Although there was a significant interaction with sex for this association, the effect of hearing aid use on incident/recurrent falls was not statistically significant among males nor females., Conclusions: A longitudinal association between the deterioration in SRTn and recurrent falls due to balance problems after 10 years was confirmed in this study. This result stresses the importance of identifying declines in hearing earlier and justifies including hearing ability assessments within fall risk prevention programs. Mixed results of hearing aid use on fall risk warrant further investigation into the temporality of this association and possible differences between men and women., (© 2024. The Author(s).)

The aim of this study was to investigate changes in sexuality and sexual dysfunction in head and neck cancer (HNC) patients in the first two years after treatment, in relation to the type of treatment. Data were used of 588 HNC patients participating in the prospective NETherlands Quality of life and Biomedical Cohort Study (NET-QUBIC) from diagnosis to 3, 6, 12 and 24 months after treatment. Primary outcome measures were the International Index of Erectile Function (IIEF) and the Female Sexual Function Index (FSFI). The total scores of the IIEF and FSFI were dichotomized into sexual (dys)function. In men, type of treatment was significantly associated with change in erectile function, orgasm, satisfaction with intercourse, and overall satisfaction. In women, type of treatment was significantly associated with change in desire, arousal, and orgasm. There were significant differences between treatment groups in change in dysfunctional sexuality. A deterioration in sexuality and sexual dysfunction from baseline to 3 months after treatment was observed especially in patients treated with chemoradiation. Changes in sexuality and sexual dysfunction in HNC patients were related to treatment, with an acute negative effect of chemoradiation. This effect on the various domains of sexuality seems to differ between men and women.

Purpose: Thermal ablation is widely recognized as the standard of care for small-size unresectable colorectal liver metastases (CRLM). For larger CRLM safety, local control and overall efficacy are not well established and insufficiently validated. The purpose of this comparative series was to analyze outcomes for intermediate-size versus small-size CRLM., Material and Methods: Patients treated with thermal ablation between December 2000 and November 2021 for small-size and intermediate-size CRLM were included. The primary endpoints were complication rate and local control (LC). Secondary endpoints included local tumor progression-free survival (LTPFS) and overall survival (OS)., Results: In total, 59 patients were included in the intermediate-size (3-5 cm) group and 221 in the small-size (0-3 cm) group. Complications were not significantly different between the two groups ( p = 0.546). No significant difference between the groups was found in an overall comparison of OS (HR 1.339; 95% CI 0.824-2.176; p = 0.239). LTPFS (HR 3.388; p < 0.001) and LC (HR 3.744; p = 0.004) were superior in the small-size group. Nevertheless, the 1-, 3-, and 5-year LC for intermediate-size CRLM was still 93.9%, 85.4%, and 81.5%, and technical efficacy improved over time., Conclusions: Thermal ablation for intermediate-size unresectable CRLM is safe and induces long-term LC in the vast majority. The results of the COLLISION-XL trial (unresectable colorectal liver metastases: stereotactic body radiotherapy versus microwave ablation-a phase II randomized controlled trial for CRLM 3-5 cm) are required to provide further clarification of the role of local ablative methods for intermediate-size unresectable CRLM.

Purpose: Personal continuity between patient and physician is a core value of primary care. Although previous studies suggest that personal continuity is associated with fewer potentially inappropriate prescriptions, evidence on continuity and prescribing in primary care is scarce. We aimed to determine the association between personal continuity and potentially inappropriate prescriptions, which encompasses potentially inappropriate medications (PIMs) and potential prescribing omissions (PPOs), by family physicians among older patients., Methods: We conducted an observational cohort study using routine care data from patients enlisted in 48 Dutch family practices from 2013 to 2018. All 25,854 patients aged 65 years and older having at least 5 contacts with their practice in 6 years were included. We calculated personal continuity using 3 established measures: the usual provider of care measure, the Bice-Boxerman Index, and the Herfindahl Index. We used the Screening Tool of Older Person's Prescriptions (STOPP) and the Screening Tool to Alert doctors to Right Treatment (START) specific to the Netherlands version 2 criteria to calculate the prevalence of potentially inappropriate prescriptions. To assess associations, we conducted multilevel negative binomial regression analyses, with and without adjustment for number of chronic conditions, age, and sex., Results: The patients' mean (SD) values for the usual provider of care measure, the Bice-Boxerman Continuity of Care Index, and the Herfindahl Index were 0.70 (0.19), 0.55 (0.24), and 0.59 (0.22), respectively. In our population, 72.2% and 74.3% of patients had at least 1 PIM and PPO, respectively; 30.9% and 34.2% had at least 3 PIMs and PPOs, respectively. All 3 measures of personal continuity were positively and significantly associated with fewer potentially inappropriate prescriptions., Conclusions: A higher level of personal continuity is associated with more appropriate prescribing. Increasing personal continuity may improve the quality of prescriptions and reduce harmful consequences., (© 2023 Annals of Family Medicine, Inc.)

Background: Patients with haematological malignancies have impaired antibody responses to SARS-CoV-2 vaccination. We aimed to investigate whether a fourth mRNA COVID-19 vaccination improved antibody quantity and quality., Methods: In this cohort study, conducted at 5 sites in the Netherlands, we compared antibody concentrations 28 days after 4 mRNA vaccinations (3-dose primary series plus 1 booster vaccination) in SARS-CoV-2 naive, immunocompromised patients with haematological malignancies to those obtained by age-matched, healthy individuals who had received the standard primary 2-dose mRNA vaccination schedule followed by a first booster mRNA vaccination. Prior to and 4 weeks after each vaccination, peripheral blood samples and data on demographic parameters and medical history were collected. Concentrations of antibodies that bind spike 1 (S1) and nucleocapsid (N) protein of SARS-CoV-2 were quantified in binding antibody units (BAU) per mL according to the WHO International Standard for COVID-19 serological tests. Seroconversion was defined as an S1 IgG concentration >10 BAU/mL and a previous SARS-CoV-2 infection as N IgG >14.3 BAU/mL. Antibody neutralising activity was tested using lentiviral-based pseudoviruses expressing spike protein of SARS-CoV-2 wild-type (D614G), Omicron BA.1, and Omicron BA.4/5 variants. This study is registered with EudraCT, number 2021-001072-41., Findings: Between March 24, 2021 and May 4, 2021, 723 patients with haematological diseases were enrolled, of which 414 fulfilled the inclusion criteria for the current analysis. Although S1 IgG concentrations in patients significantly improved after the fourth dose, they remained significantly lower compared to those obtained by 58 age-matched healthy individuals after their first booster (third) vaccination. The rise in neutralising antibody concentration was most prominent in patients with a recovering B cell compartment, although potent responses were also observed in patients with persistent immunodeficiencies. 19% of patients never seroconverted, despite 4 vaccinations. Patients who received their first 2 vaccinations when they were B cell depleted and the third and fourth vaccination during B cell recovery demonstrated similar antibody induction dynamics as patients with normal B cell numbers during the first 2 vaccinations. However, the neutralising capacity of these antibodies was significantly better than that of patients with normal B cell numbers after two vaccinations., Interpretation: A fourth mRNA COVID-19 vaccination improved S1 IgG concentrations in the majority of patients with a haematological malignancy. Vaccination during B cell depletion may pave the way for better quality of antibody responses after B cell reconstitution., Funding: The Netherlands Organisation for Health Research and Development and Amsterdam UMC., Competing Interests: T.M. received research grants from Celgene/BMS, Genentech, and Siemens, and received consulting fees from Kite/Gilead, Janssen, Lilly (all payments made to institution). All other authors declare no competing financial interests., (© 2023 The Author(s).)

Background: Neurofilament light (NfL) has been identified as a biomarker for neuroaxonal damage in preterm infants, but its relation with bronchopulmonary dysplasia (BPD) has not been established. We hypothesized that BPD is associated with increased NfL levels at an early stage, indicative of early neuroaxonal damage., Methods: We included preterm infants born <30 weeks of gestation for assessment of NfL levels from cord blood and blood obtained at postnatal days 3, 7, 14, and 28. We used linear regression analysis to compare NfL levels between infants with moderate/severe BPD and infants with no/mild BPD, and linear mixed model analysis to compare the effect of time on NfL levels between groups., Results: Sixty-seven infants with a gestational age (GA) of 27 ± 1.3 weeks were included for analysis, of whom 19 (28%) developed moderate/severe BPD. Although NfL levels were higher at every time point in infants with BPD, statistical significance was lost after adjustment for GA, small for gestational age (SGA) and intraventricular hemorrhage (IVH). Groups did not differ in NfL change over time., Conclusions: The positive association between BPD and NfL in the first weeks of life could be explained by GA, SGA and IVH rather than by development of BPD., Impact: Neurofilament light chain (NfL) is a known biomarker for neuroaxonal damage. Biomarkers for brain damage during the first weeks of life in preterm infants developing BPD are lacking. NfL levels obtained during the first weeks of life did not differ between infants with and without BPD in analyses adjusted for GA, SGA, and IVH., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Study Question: Does a short interval (i.e. ≤90 min), compared to a long interval (i.e. ≥180 min), between semen collection and intrauterine insemination (IUI) increase the cumulative chance of an ongoing pregnancy after six IUI cycles?, Summary Answer: A long interval between semen collection and IUI resulted in a borderline significant improvement in cumulative ongoing pregnancies and a statistically significant shorter time to pregnancy., What Is Known Already: Retrospective studies assessing the effect of the time interval between semen collection and IUI on pregnancy outcomes have shown inconclusive results. Some studies have indicated a beneficial effect of a short interval between semen collection and IUI on IUI outcomes, while others have not found any differences. To date, no prospective trials have been published on this subject., Study Design, Size, Duration: The study was performed as a non-blinded, single-center RCT with 297 couples undergoing IUI treatment in a natural or stimulated cycle. The study was conducted between February 2012 and December 2018., Participants/materials, Setting, Methods: Couples with unexplained or mild male subfertility and an indication for IUI were randomly assigned for up to six IUI cycles into either the control group (long interval, i.e. 180 min or more between semen collection and insemination) or the study group (short interval, i.e. insemination as soon as possible after semen processing and within 90 min of semen collection). The study was carried out in an academic hospital-based IVF center in the Netherlands. The primary endpoint of the study was ongoing pregnancy rate per couple, defined as a viable intrauterine pregnancy at 10 weeks after insemination., Main Results and the Role of Chance: In the short interval group, 142 couples were analyzed versus 138 couples in the long interval group. In the intention-to-treat (ITT) analysis, the cumulative ongoing pregnancy rate was significantly higher in the long interval group (71/138; 51.4%) compared to that in the short interval group (56/142; 39.4%; relative risks 0.77; 95% CI 0.59-0.99; P = 0.044). The time to pregnancy was significantly shorter in the long interval group (log-rank test, P = 0.012). A Cox regression analysis showed similar results (adjusted hazard ratio 1.528, 95% CI 1.074-2.174, P = 0.019)., Limitations, Reasons for Caution: Limitations of our study are the non-blinded design, the long inclusion and follow-up period of nearly seven years and the large number of protocol violations, especially because they predominantly occurred in the short interval group. The non-significant results in the per-protocol (PP) analyses and the weaknesses of the study should be taken into account in the assessment of the borderline significance of the results in the ITT analyses., Wider Implications of the Findings: Because it is not necessary to perform the IUI immediately after semen processing, there can be more time available to choose the optimum work-flow and clinic occupancy. Clinics and laboratories should find their optimal timing of insemination, considering the time between human chorionic gonadotropin injection and insemination in relation to the sperm preparation techniques used as well as the storage time and conditions until insemination., Study Funding/competing Interest(s): There were no external funding and no competing interests to declare., Trial Registration Number: Dutch trial registry, trial registration number NTR3144., Trial Registration Date: 14 November 2011., Date of First Patient’s Enrollment: 5 February 2012., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

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.)

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.

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).)

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.)

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.

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: 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).)

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).)

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).

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.)

Thermal ablation and stereotactic ablative radiotherapy (SABR) are techniques to eradicate colorectal liver metastases (CRLM). This study compares the safety, efficacy and long-term oncological outcomes of these treatment methods. All prospectively registered patients (AmCORE registry) treated with thermal ablation or SABR alone for unresectable CRLM between 2007 and 2020 were analyzed using multivariate Cox-proportional hazard regression. In total 199 patients were included for analysis: 144 (400 CRLM) thermal ablation; 55 (69 CRLM) SABR. SABR patients were characterized by older age ( p = 0.006), extrahepatic disease at diagnosis ( p = 0.004) and larger tumors ( p < 0.001). Thermal ablation patients were more likely to have synchronous disease, higher clinical risk scores ( p = 0.030) and higher numbers of CRLMs treated ( p < 0.001). Mortality was zero and morbidity low in both groups: no serious adverse events were recorded following SABR ( n = 0/55) and nine ( n = 9/144 [6.3%]; all CTCAE grade 3) after thermal ablation. SABR was associated with an inferior overall survival (OS) (median OS 53.0 months vs. 27.4 months; HR = 1.29, 95% CI 1.12-1.49; p = 0.003), local tumor progression-free survival (LTPFS) per-tumor (HR = 1.24, 95% CI 1.01-1.52; p = 0.044) and local control per-patient (HR = 1.57, 95% CI 1.20-2.04; p = 0.001) and per-tumor (HR = 1.89, 95% CI 1.44-2.49; p < 0.001). In this study thermal ablation was superior to SABR with regard to OS, LTPFS and local control, albeit at the cost of a limited risk of serious adverse events. Further studies are required to assess whether the worse outcomes following SABR were the effect of true differences in ablative treatment or a result of residual confounding.

The aim of this study was to assess primary tumor sidedness of colorectal cancer (CRC), rat sarcoma viral oncogene homolog (RAS) and v-raf murine sarcoma viral oncogene homolog B (BRAF) mutations and microsatellite instability (MSI) status as prognostic factors predicting complications, survival outcomes, and local tumor progression (LTP) following surgery and thermal ablation in patients with colorectal liver metastases (CRLM). This Amsterdam Colorectal Liver Met Registry (AmCORE) based study included 520 patients, 774 procedures, and 2101 tumors undergoing local treatment (resection and/or thermal ablation) from 2000 to 2021. Outcomes following local treatment were analyzed for primary tumor sidedness of CRC, RAS, and BRAF mutations and MSI status. The Kaplan-Meier method was used to estimate local tumor progression-free survival (LTPFS), local control (LC), distant progression-free survival (DPFS), and overall survival (OS). Uni- and multivariable analyses were performed based on Cox proportional hazards model. The chi-square test was used to analyze complications. Complications ( p = 0.485), OS ( p = 0.252), LTPFS ( p = 0.939), and LC ( p = 0.423) was not associated with tumor-sidedness. Compared to right-sided colon cancer (CC) (reference HR 1.000), DPFS was superior for left-sided CC and rectal cancer ( p = 0.018) with an HR for left-sided CC of 0.742 (95% CI, 0.596-0.923) and for RC of 0.760 (95% CI, 0.597-0.966). Regarding RAS mutations, no significant difference was found in OS ( p = 0.116). DPFS ( p = 0.001), LTPFS ( p = 0.039), and LC ( p = 0.025) were significantly lower in the RAS mutation group. Though no difference in LTPFS was found between RAS wildtype and RAS mutated CRLM following resection ( p = 0.532), LTPFS was worse for RAS mutated tumors compared to RAS wildtype following thermal ablation ( p = 0.037). OS was significantly lower in the BRAF mutation group ( p < 0.001) and in the MSI group ( p < 0.001) following local treatment, while both did not affect DPFS, LTPFS, and LC. This AmCORE based study suggests the necessity of wider margins to reduce LTP rates in patients with RAS mutated CRLM, especially for thermal ablation. Upfront knowledge regarding molecular biomarkers may contribute to improved oncological outcomes.

Objective: Evaluation of the management and survival in patients treated for temporal bone squamous cell carcinoma (TBSCC) in a tertiary referral centre., Methods: Forty-nine patients underwent primary treatment for TBSCC. Thirty-six patients underwent a lateral temporal bone resection (LTBR) or subtotal temporal bone resection (STBR). Overall survival (OS) and disease-specific survival (DSS) analysis were assessed., Results: Five-year OS of the 49 patients was 39%. Five-year OS of the 36 patients who underwent LTBR or STBR was 46%. Tumour-free margins were achieved in all patients with T1 and T2 disease, in 59% patients with T3 tumours and 0% patients with T4 disease. Five-year DSS was 85% for all T1/T2 tumours, 53% for T3 tumours and 0% for T4 tumours. Clear resection margins was the only significant predictor of DSS in our cohort., Conclusions: The mainstay of treatment for TBSCC is temporal bone resection with tumour free resection margins, with or without adjuvant radiotherapy. Survival is negatively influenced by non-radical resection. T1 and T2 tumours can be managed safely with LTBR. More advanced disease requires a more extensive resection, with a higher likelihood of non-radical resections and decreased survival rates., (Copyright © 2021 Società Italiana di Otorinolaringoiatria e Chirurgia Cervico-Facciale, Rome, Italy.)

Introduction: The web-based self-management application Oncokompas was developed to support cancer survivors to monitor health-related quality of life and symptoms (Measure) and to provide tailored information (Learn) and supportive care options (Act). In a previously reported randomised controlled trial (RCT), 68% of 655 recruited survivors were eligible, and of those 45% participated in the RCT. Among participants of the RCT that were randomised to the intervention group, 52% used Oncokompas as intended. The aim of this study was to explore reasons for not participating in the RCT, and reasons for not using Oncokompas among non-users, and the use and evaluation of Oncokompas among users., Methods: Reasons for not participating were assessed with a study-specific questionnaire among 243 survivors who declined participation. Usage was investigated among 320 participants randomised to the intervention group of the RCT via system data and a study-specific questionnaire that was assessed during the 1 week follow-up (T1) assessment., Results: Main reasons for not participating were not interested in participation in scientific research (40%) and not interested in scientific research and Oncokompas (28%). Main reasons for not being interested in Oncokompas were wanting to leave the period of being ill behind (29%), no symptom burden (23%), or lacking internet skills (18%). Out of the 320 participants in the intervention group 167 (52%) used Oncokompas as intended. Among 72 non-users, main reasons for not using Oncokompas were no symptom burden (32%) or lack of time (26%). Among 248 survivors that activated their account, satisfaction and user-friendliness were rated with a 7 (scale 0-10). Within 3 (IQR 1-4) sessions, users selected 32 (IQR 6-37) topics. Main reasons for not using healthcare options in Act were that the information in Learn was already sufficient (44%) or no supportive care needs (32%)., Discussion: Main reasons for not reaching or using Oncokompas were no symptom burden, no supportive care needs, or lack of time. Users selected many cancer-generic and tumour-specific topics to address, indicating added value of the wide range of available topics., Competing Interests: IMV-dL has received grants from the Dutch Cancer Society (KWF Kankerbestrijding), Pink Ribbon, the Netherlands Organization for Health Research and Development (ZonMW), the SAG Foundation–Zilveren Kruis Health Care Assurance Company, Danone Ecofund–Nutricia, Red-kite (distributor of eHealth tools), and Bristol-Myers Squibb, during the conduct of this study. CRL has received personal fees for global advisory board participation from MSD, during the conduct of this study. All other authors have no conflicts of interest., (© 2021 The Authors.)

The aim of this study was to assess safety, efficacy and survival outcomes of repeat thermal ablation as compared to repeat partial hepatectomy in patients with recurrent colorectal liver metastases (CRLM). This Amsterdam Colorectal Liver Met Registry (AmCORE) based study of two cohorts, repeat thermal ablation versus repeat partial hepatectomy, analyzed 136 patients (100 thermal ablation, 36 partial hepatectomy) and 224 tumors (170 thermal ablation, 54 partial hepatectomy) with recurrent CRLM from May 2002 to December 2020. The primary and secondary endpoints were overall survival (OS), distant progression-free survival (DPFS) and local tumor progression-free survival (LTPFS), estimated using the Kaplan-Meier method, and complications, analyzed using the chi-square test. Multivariable analyses based on Cox proportional hazards model were used to account for potential confounders. In addition, subgroup analyses according to patient, initial and repeat local treatment characteristics were performed. In the crude overall comparison, OS of patients treated with repeat partial hepatectomy was not statistically different from repeat thermal ablation ( p = 0.927). Further quantification of OS, after accounting for potential confounders, demonstrated concordant results for repeat local treatment (hazard ratio (HR), 0.986; 95% confidence interval (CI), 0.517-1.881; p = 0.966). The 1-, 3- and 5-year OS were 98.9%, 62.6% and 42.3% respectively for the thermal ablation group and 93.8%, 74.5% and 49.3% for the repeat resection group. No differences in DPFS ( p = 0.942), LTPFS ( p = 0.397) and complication rate ( p = 0.063) were found. Mean length of hospital stay was 2.1 days in the repeat thermal ablation group and 4.8 days in the repeat partial hepatectomy group ( p = 0.009). Subgroup analyses identified no heterogeneous treatment effects according to patient, initial and repeat local treatment characteristics. Repeat partial hepatectomy was not statistically different from repeat thermal ablation with regard to OS, DPFS, LTPFS and complications, whereas length of hospital stay favored repeat thermal ablation. Thermal ablation should be considered a valid and potentially less invasive alternative for small-size (0-3 cm) CRLM in the treatment of recurrent new CRLM. While, the eagerly awaited results of the phase III prospective randomized controlled COLLISION trial (NCT03088150) should provide definitive answers regarding surgery versus thermal ablation for CRLM.

Background Irreversible electroporation (IRE), an ablative technique that uses high-voltage electrical pulses, has shown promise for eradicating tumors near critical structures, including blood vessels and bile ducts. Purpose To investigate the efficacy and safety of IRE for colorectal liver metastases (CRLMs) unsuitable for resection or thermal ablation because of proximity to critical structures and for further systemically administered treatments. Materials and Methods Between June 2014 and November 2018, participants with fluorine 18 ( 18 F) fluorodeoxyglucose (FDG) PET-avid CRLMs measuring 5.0 cm or smaller, unsuitable for partial hepatectomy and thermal ablation, underwent percutaneous or open IRE (ClinicalTrials.gov identifier: NCT02082782). Follow-up included tumor marker assessment and 18 F-FDG PET/CT imaging. For the primary end point to be met, at least 50% of treated participants had to be alive without local tumor progression (LTP) at 12 months, defined as LTP-free survival. Secondary aims were safety, technical success, local control allowing for repeat procedures, disease-free status, and overall survival. Results A total of 51 participants (median age, 67 years [interquartile range, 62-75 years]; 37 men) underwent IRE. Of these 51 participants, 50 with a total of 76 CRLMs (median tumor size, 2.2 cm; range, 0.5-5.4 cm) were successfully treated in 62 procedures; in one participant, treatment was stopped prematurely because of pulse-induced cardiac arrhythmia. With a per-participant 1-year LTP-free survival of 68% (95% CI: 59, 84) according to competing risk analysis, the primary end point was met. Local control following repeat procedures was achieved in 74% of participants (37 of 50). Median overall survival from first IRE was 2.7 years (95% CI: 1.6, 3.8). Twenty-three participants experienced a total of 34 adverse events in 25 of the 62 procedures (overall complication rate, 40%). One participant (2%), who had an infected biloma after IRE, died fewer than 90 days after the procedure (grade 5 adverse event). Conclusion Irreversible electroporation was effective and relatively safe for colorectal liver metastases 5.0 cm or smaller that were unsuitable for partial hepatectomy, thermal ablation, or further systemic treatment. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Goldberg in this issue.

Aims: Prescribing medication is a complex process that, when done inappropriately, can lead to adverse drug events, resulting in patient harm and hospital admissions. Worldwide cost is estimated at 42 billion USD each year. Despite several efforts in the past years, medication-related harm has not declined. The aim was to determine whether a prescriber-focussed participatory action intervention, initiated by a multidisciplinary pharmacotherapy team, is able to reduce the number of in-hospital prescriptions containing ≥1 prescribing error (PE), by identifying and reducing challenges in appropriate prescribing., Methods: A prospective single-centre before- and after study was conducted in an academic hospital in the Netherlands. Twelve clinical wards (medical, surgical, mixed and paediatric) were recruited., Results: Overall, 321 patients with a total of 2978 prescriptions at baseline were compared with 201 patients with 2438 prescriptions postintervention. Of these, m456 prescriptions contained ≥1 PE (15.3%) at baseline and 357 prescriptions contained ≥1 PEs (14.6%) postintervention. PEs were determined in multidisciplinary consensus. On some study wards, a trend toward a decreasing number of PEs was observed. The intervention was associated with a nonsignificant difference in PEs (incidence rate ratio 0.96, 95% confidence interval 0.83-1.10), which was unaltered after correction. The most important identified challenges were insufficient knowledge beyond own expertise, unawareness of guidelines and a heavy workload., Conclusion: The tailored interventions developed with and implemented by stakeholders led to a statistically nonsignificant reduction in inappropriate in-hospital prescribing after a 6-month intervention period. Our prescriber-focussed participatory action intervention identified challenges in appropriate in-hospital prescribing on prescriber- and organizational level., (© 2020 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Introduction: A recent randomized controlled trial (RCT) in patients with head and neck cancer (HNC) with psychological distress showed that a stepped care (SC) program targeting psychological distress compared with care as usual (CAU), is (cost)effective in reducing psychological distress., Aim: The aim of the present study was to investigate whether SC can coalleviate problems with sexual interest and enjoyment. A secondary aim was to investigate whether the presence of an unmet sexual health need and having a psychiatric disorder (depression or anxiety) at baseline moderated any effect of SC on these sexual variables until 1-year follow-up., Methods: HNC survivors (N = 134), randomized to SC or CAU, were assessed regarding their sexual interest and enjoyment before and after the intervention and at 3, 6, 9, and 12 months follow-up. Linear mixed models were used to evaluate differences in the course of sexual interest and enjoyment between SC and CAU., Main Outcome Measure: The "sexuality" symptom subscale, part of the European Organization for Research and Treatment of Cancer, Quality of Life Questionnaire, Head and Neck Cancer-specific module., Results: Of all patients, 76.1% had an unmet sexual need at baseline, 24.6% had a psychiatric disorder (anxiety or depression). SC did not reduce problems with sexual interest and enjoyment at any of the follow-up measurements compared with CAU (P = .85). This was neither moderated by an unmet sexual health need at baseline (P = .64) nor by the presence of a psychiatric disorder at baseline (P = .59)., Conclusion: A substantial number of patients with HNC have unmet sexual health needs. SC targeting psychological distress does not reduce problems with sexuality in these patients. Interventions specifically targeting sexuality are recommended. Schutte LER, Melissant HC, Jansen F, et al. Effect of Stepped Care on Sexual Interest and Enjoyment in Distressed Patients with Head and Neck Cancer: A Randomized Controlled Trial. Sex Med 2021;9:100304., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Rationale: Thalamus atrophy has been linked to cognitive decline in multiple sclerosis (MS) using various segmentation methods. We investigated the consistency of the association between thalamus volume and cognition in MS for two common automated segmentation approaches, as well as fully manual outlining., Methods: Standardized neuropsychological assessment and 3-Tesla 3D-T1-weighted brain MRI were collected (multi-center) from 57 MS patients and 17 healthy controls. Thalamus segmentations were generated manually and using five automated methods. Agreement between the algorithms and manual outlines was assessed with Bland-Altman plots; linear regression assessed the presence of proportional bias. The effect of segmentation method on the separation of cognitively impaired (CI) and preserved (CP) patients was investigated through Generalized Estimating Equations; associations with cognitive measures were investigated using linear mixed models, for each method and vendor., Results: In smaller thalami, automated methods systematically overestimated volumes compared to manual segmentations [ρ=(-0.42)-(-0.76); p-values < 0.001). All methods significantly distinguished CI from CP MS patients, except manual outlines of the left thalamus (p = 0.23). Poorer global neuropsychological test performance was significantly associated with smaller thalamus volumes bilaterally using all methods. Vendor significantly affected the findings., Conclusion: Automated and manual thalamus segmentation consistently demonstrated an association between thalamus atrophy and cognitive impairment in MS. However, a proportional bias in smaller thalami and choice of MRI acquisition system might impact the effect size of these findings., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)