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OBJECTIVE: Older adults at the Emergency Department (ED) often present with nonspecific complaints (NSC) such as 'weakness' or 'feeling unwell'. Health care workers may underestimate illness in patients with NSC, leading to adverse health outcomes. This study compares characteristics and outcomes of NSC-patients versus specific complaints (SC) patients.METHODS: Cohort study in patients ≥ 70 years in two Dutch EDs. NSC was classified according to the BANC-study-framework based on the medical history in the ED letter, before additional diagnostics took place. A second classification was performed at the end of the ED visit/hospital admission. Primary outcomes were functional decline, institutionalization, and mortality at 30 days.RESULTS: 26% (n = 228) of a total of 888 included patients presented with NSC. Compared with SC-patients, NSC-patients were older, more frail, and more frequently female. NSC-patients had a higher risk of functional decline and institutionalization at 30 days (adjusted ORs 1.84, 95% CI 1.27 - 2.72, and 2.46, 95% CI 1.51-4.00, respectively), but not mortality (adjusted OR 1.26, 95% CI 0.58 - 2.73). Reclassification to a specific complaint after the ED visit or hospital admission occurred in 54% of NSC-patients.CONCLUSION: NSC occur especially in older, frail female patients and are associated with an increased risk of functional decline and institutionalization, even after adjustment for worse baseline status. In half of the patients, a specific complaint revealed during ED or hospital stay. Physicians at the ED should consider NSC as a red flag needing appropriate observation and evaluation of underlying serious conditions and needs of this vulnerable patient group.

Background: Carriers of multidrug-resistant bacteria are at risk of infections with these bacteria; the precise size of this risk is unclear. We aimed to quantify the effect of gut colonisation on subsequent risk of infection with multidrug-resistant bacteria. Methods: We performed a systematic review and meta-regression analysis. We searched PubMed, Embase, Web of Science Core Collection, and Google Scholar for follow-up studies published from Jan 1, 1995, to March 17, 2022, that measured the incidence of infections with multidrug-resistant Gram-negative bacteria (MDR-GNB) and from Jan 1, 1995, to March 15, 2022, that measured the incidence of infections with vancomycin-resistant enterococci (VRE). We included original cohort studies and case-control studies that used incidence-density sampling, included 50 or more patients with enteric colonisation or positive urinary samples as a surrogate marker of colonisation, or both, and analysed infections clearly preceded by colonisation. We did not use any language restrictions. We excluded studies not reporting length of follow-up. Summary data were extracted and independently cross-verified by two authors. Carriage was defined as MDR-GNB or VRE, detected in faecal or urinary cultures. Our primary outcomes were cumulative incidence and incidence density of infection in patients colonised by multidrug-resistant bacteria. To estimate pooled incidences, general linearised mixed-effects meta-regressions were used, adjusting for varying follow-up durations. This study is registered with PROSPERO, CRD42020222415. Findings: Of the 301 studies identified, 44 studies (26 on MDR-GNB, 14 on VRE, and four on both MDR-GNB and VRE) from 14 countries were retained for qualitative synthesis, 40 of which were analysed with meta-regression, comprising data for 14 049 patients colonised with multidrug-resistant bacteria. The pooled cumulative incidence of infection was 14% (95% CI 10–18; p

In the original publication, one of the co-author names was mistakenly misspelled as "Jan Hazelet" instead of "Jan Hazelzet". It is updated in this correction.

BackgroundThe majority of patients with multiple sclerosis on ocrelizumab have B-cell depletion after standard interval dosing of 26 weeks. With B-cell-guided dosing patients receive their next dose when B-cell repopulation occurs. Prediction of B-cell repopulation using ocrelizumab concentrations could aid in personalising treatment regimes. The objectives of this study were to evaluate the association between ocrelizumab drug concentration, antidrug antibodies (ADAs) and CD19 B-cell count, and to define a cut-off ocrelizumab concentration for start of B-cell repopulation (defined by ≥10 CD19+ B cells/µL).MethodsIn this investigator-initiated prospective study, blood samples at various time points during ocrelizumab treatment were collected from a biobank. Serum ocrelizumab concentrations and ADAs were measured with two different assays developed for this study. Data were analysed using linear mixed effect models. An receiver operating characteristic (ROC) curve was used to determine a cut-off ocrelizumab concentration for start of B-cell repopulation (defined by ≥10 cells/µL).ResultsA total of 452 blood samples from 72 patients were analysed. Ocrelizumab concentrations were detectable up until 53.3 weeks after last infusion and ranged between ConclusionsSerum ocrelizumab concentration was strongly associated with B-cell count. Measurement of ocrelizumab drug concentrations and ADAs could play an important role to further personalise treatment and predict the start of B-cell repopulation.

Background: In heart failure (HF), symptoms and health-related quality of life (HRQoL) are known to vary among different HF subgroups, but evidence on the association between changing HRQoL and outcomes has not been evaluated. Objectives: The authors sought to investigate the relationship between changing symptoms, signs, and HRQoL and outcomes by sex, ethnicity, and socioeconomic status (SES). Methods: Using the ASIAN-HF (Asian Sudden Cardiac Death in Heart Failure) Registry, we investigated associations between the 6-month change in a “global” symptoms and signs score (GSSS), Kansas City Cardiomyopathy Questionnaire overall score (KCCQ-OS), and visual analogue scale (VAS) and 1-year mortality or HF hospitalization. Results: In 6,549 patients (mean age: 62 ± 13 years], 29% female, 27% HF with preserved ejection fraction), women and those in low SES groups had higher symptom burden but lower signs and similar KCCQ-OS to their respective counterparts. Malay patients had the highest GSSS (3.9) and lowest KCCQ-OS (58.5), and Thai/Filipino/others (2.6) and Chinese patients (2.7) had the lowest GSSS scores and the highest KCCQ-OS (73.1 and 74.6, respectively). Compared to no change, worsening of GSSS (>1-point increase), KCCQ-OS (≥10-point decrease) and VAS (>1-point decrease) were associated with higher risk of HF admission/death (adjusted HR: 2.95 [95% CI: 2.14-4.06], 1.93 [95% CI: 1.26-2.94], and 2.30 [95% CI: 1.51-3.52], respectively). Conversely, the same degrees of improvement in GSSS, KCCQ-OS, and VAS were associated with reduced rates (HR: 0.35 [95% CI: 0.25-0.49], 0.25 [95% CI: 0.16-0.40], and 0.64 [95% CI: 0.40-1.00], respectively). Results were consistent across all sex, ethnicity, and SES groups (interaction P > 0.05). Conclusions: Serial measures of patient-reported symptoms and HRQoL are significant and consistent predictors of outcomes among different groups with HF and provide the potential for a patient-centered and pragmatic approach to risk stratification.

Objectives: The aim of this study was to assess associations between socio-demographic characteristics and dental costs of children living in Amsterdam. Having incurred dental costs was an indicator for having visited the dentist. Having incurred low or high dental costs may indicate the type of dental care provided (periodic examination, preventive care or restorative treatment). Methods: This study followed a cross-sectional, observational design. The research population contained all children up until 17 years living in Amsterdam in 2016. Dental costs from all Dutch healthcare insurance companies were obtained via Vektis, and socio-demographic data were obtained from Statistics Netherlands (CBS). The study population was stratified into age groups: 0–4 and 5–17 years. Dental costs were classified as no dental costs (0 euros), low dental costs (>0 to

Objective The aim of this study was to investigate the effect of treat-to-target combination therapy with intensification at 13 weeks in early RA. Methods Early RA patients were classified as being at high or low risk of worsening RA based on disease activity and prognostic factors. High-risk patients received COBRA-light (prednisolone 30 mg/day tapered to 7.5 mg/day, MTX increasing to 25 mg/week), and low-risk patients received MTX monotherapy increasing to 25 mg/week. The primary outcome (target) was DAS44 Results In the high-risk group (n = 150), 110 patients (73%) reached the target at 13 weeks, and 9 dropped out. Non-responders were randomized to intensification (n = 15) or continuation (n = 16), and after 26 weeks, 12 (80%) vs 7 (44%) of these, respectively, reached the target [difference: 36%, (95% CI 2%, 71%); P = 0.04]. In the low-risk group (n = 40), 17 (43%) reached the target. Non-responders were randomized to intensification (n = 8) or continuation (n = 7); 4 vs 3, respectively, reached the target. Adverse event rates were higher in the high-risk group, and higher in the intensification subgroup of that group. Serious adverse events were rare. Protocol violations were frequent and mostly led to mitigation of actual treatment intensification. Conclusion Initial combination therapy was very successful in high-risk RA, and early intensification was beneficial in patients not reaching the strict target. The low-risk group was too small for drawing conclusions. In routine practice, adherence to early intensification based on strict targets is difficult. Trial registration Netherlands Trial Register (NTR), NL4393, https://www.trialregister.nl/.

Introduction: Endovascular treatment (EVT) has been proven to be both effective and cost-effective for patients with acute ischaemic stroke. We investigated the budget impact of large-scale implementation of EVT for acute ischaemic stroke patients in the Netherlands for 2015–2021. Methods: An analysis was performed from a healthcare perspective as a preplanned substudy of the Multicenter Randomized Clinical trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN). Estimated yearly costs during follow-up after stroke for patients who had or had not been treated with EVT as add-on to usual care were linked to numbers of new patients retrieved from 2 Dutch registries of EVT that started after the last inclusion in MR CLEAN (2014). Aggregated costs and costs per care sector were calculated based on prevalence using a population dynamic tool. Results: From 2015, the yearly number of new acute ischaemic stroke patients receiving EVT increased almost threefold, from 812 in 2015 to 2,370 in 2021. The introduction of EVT plus usual care resulted in estimated net annual savings that increased from € 2.9 million in 2015 to € 58 million in 2021. Conclusion: Offering EVT as add-on to usual care for acute ischaemic stroke patients was increasingly cost saving from a national healthcare perspective but affected distinct healthcare sectors differently.

A major challenge of genome-wide association studies (GWASs) is to translate phenotypic associations into biological insights. Here, we integrate a large GWAS on blood lipids involving 1.6 million individuals from five ancestries with a wide array of functional genomic datasets to discover regulatory mechanisms underlying lipid associations. We first prioritize lipid-associated genes with expression quantitative trait locus (eQTL) colocalizations and then add chromatin interaction data to narrow the search for functional genes. Polygenic enrichment analysis across 697 annotations from a host of tissues and cell types confirms the central role of the liver in lipid levels and highlights the selective enrichment of adipose-specific chromatin marks in high-density lipoprotein cholesterol and triglycerides. Overlapping transcription factor (TF) binding sites with lipid-associated loci identifies TFs relevant in lipid biology. In addition, we present an integrative framework to prioritize causal variants at GWAS loci, producing a comprehensive list of candidate causal genes and variants with multiple layers of functional evidence. We highlight two of the prioritized genes, CREBRF and RRBP1, which show convergent evidence across functional datasets supporting their roles in lipid biology. Xiang Zhu is supported by the Stein Fellowship from Stanford University and Institute for Computational and Data Sciences Seed Grant from The Pennsylvania State University. C.D.B. is supported by the NIH (R01-HL133218). Funding for the Global Lipids Genetics Consortium was provided by the NIH (R01-HL127564). This research was conducted using the UK Biobank Resource under application number 24460. This research is based on data from the Million Veteran Program, Office of Research and Development, Veterans Health Administration, and was supported by awards 2I01BX003362-03A1 and 1I01BX004821-01A1. This publication does not represent the views of the Department of Veteran Affairs or the United States Government. We thank Bethany Klunder for administrative support. Study-specific acknowledgments are provided in the supplemental information.

ObjectiveTo investigate the potential of whole-body positron emission tomography/computed tomography (PET/CT) with a macrophage tracer to image arthritis in patients with early rheumatoid arthritis (RA).MethodsThirty-five previously untreated, clinically active patients with early RA underwent whole-body PET/CT scanning with the macrophage tracer (R)-[11C]PK11195 in addition to clinical assessment (Disease Activity Score in 44 joints [DAS44]). Tracer uptake was assessed quantitatively as standardized uptake values (SUVs). In addition, 2 readers blinded to clinical assessment visually scored tracer uptake in joints. Clinical and PET variables were compared using Cohen , linear regression/correlation, and t tests, where appropriate.ResultsAll but 1 patient showed enhanced tracer uptake in at least 1 joint. Twelve percent of all joints (171/1470) were visually positive on the PET scan, most frequently the small joints in feet (40%) and hands (37%), followed by wrists (15%). Correlations of visual scores with clinical findings both at patient and joint levels were absent or weak. In contrast, average SUVs in the hands, feet, and whole body showed significant correlations with DAS44 scores, with the best correlation seen in the feet (R2 = 0.29, P < 0.01).ConclusionClinically active patients with early RA had increased joint uptake of a macrophage PET tracer, especially in the feet. Quantitative, but not visual PET measures of whole body and joint groups, particularly the feet, showed moderate and statistically significant correlations with clinical outcome.

Background Adenoma detection rate (ADR) is a well-established quality indicator for colonoscopy and is inversely associated with the incidence of interval post-colonoscopy colorectal cancer. However, interval post-colonoscopy colorectal cancers frequently develop from serrated polyps, which are not included in the ADR. Therefore, the proximal serrated polyp detection rate (PSPDR) has been proposed as a quality indicator, but its association with interval post-colonoscopy colorectal cancer has not been studied. We aimed to evaluate this potential association based on data collected in the Dutch colorectal cancer screening programme. Methods In this population-based study, using colonoscopy data from the Dutch faecal immunochemical test-based colorectal cancer screening programme and cancer data from the Netherlands Cancer Registry, we evaluated the association between endoscopists' individual PSPDR and their patients' risk of interval post-colonoscopy colorectal cancer with a shared frailty Cox proportional-hazard regression analysis. Participants in the screening programme who were eligible for inclusion were aged 55-76 years, had a positive faecal immunochemical test (cutoff 15 mu g Hb/g faeces at start and changed mid-2014 to 47 mu g Hb/g faeces), were asymptomatic, and underwent a colonoscopy between Jan 1, 2014, and Dec 31, 2020. The PSPDR was defined as the proportion of colonoscopies in which at least one serrated polyp proximal to the descending colon was detected, confirmed by histopathology. The ADR was defined as the proportion of all colonoscopies in which at least one conventional adenoma was detected, confirmed by histopathology. Detection rates were determined for each endoscopist individually. We additionally evaluated the risk of interval post-colonoscopy colorectal cancer for endoscopists with a PSPDR and ADR above the median versus endoscopists with either one or both parameters below the median. This study is registered with the Netherlands Trial Registry, NL8350. Findings During the study period, 329 104 colonoscopies were done, of which 277 555, done by 441 endoscopists, were included in the PSPDR calculations. The median PSPDR was 11.9% (IQR 8.3-15.8) and median ADR was 66.3% (61.4-69.9). The correlation between the PSDPR and ADR was moderate (r=0.59; p < 0middot0001). During a median follow-up of 33 months (IQR 21-42), 305 interval post-colonoscopy colorectal cancers were detected. For each percentage point increase in PSPDR, the adjusted interval post-colonoscopy colorectal cancer hazard was 7% lower (hazard ratio [HR] 0.93, 95% CI 0.90-0.95; p < 0middot0001). Compared with endoscopists with a PSPDR greater than 11middot9% and ADR greater than 66middot3%, the HR of interval post-colonoscopy colorectal cancer for endoscopists with a low PSPDR and high ADR was 1.79 (95% CI 1.22-2.63), for endoscopists with a high PSPDR and low ADR was 1.97 (1.19-3.24), and for endoscopists with a low PSPDR and low ADR was 2.55 (1.89-3.45). Gastroenterology, (Prof Gastroenterology the (Prof Interpretation The PSPDR of an endoscopist is inversely associated with the incidence of interval post-colonoscopy colorectal cancer. Implementation of PSPDR monitoring, in addition to ADR monitoring, could optimise colorectal cancer prevention. Copyright (C) 2022 Elsevier Ltd. All rights reserved.

Objectives: The anchor-based minimal important change (MIC), based on the receiver operating characteristic (ROC) analysis or predictive modeling, is biased by the proportion of improved patients. The adjusted MIC, published in 2017, adjusts the predictive MIC for this bias but does not take the reliability of the transition ratings (i.e., the anchor) into account. The aim of this study was to examine whether the transition ratings reliability affects the accuracy of the adjusted MIC and, if so, whether the adjustment can be improved. Study Design and Setting: Multiple simulations of patient samples involved in anchor-based MIC studies with different characteristics of patient-reported outcome scores were used to determine the impact of reliability of the transition ratings on the MIC estimate. An improved adjustment formula was derived in an exploration set of simulated samples (number of samples = 19,440) and validated in a different set of simulated samples (number of samples = 12,960). The effect of sample size (100–1,000) was also evaluated in simulated datasets. Results: Reliability of the transition ratings biased the MIC estimate if the proportion improved was different from 0.5. The improved adjustment formula performed well, especially if the proportion improved was between 0.3 and 0.7. Smaller sample sizes were at the expense of the precision of the MIC estimates. Conclusion: We provide an improved formula for calculating the adjusted MIC, taking into account the proportion of improved patients and the reliability of the transition ratings.

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 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.

Background There is increasing evidence that the food environment, i.e. the availability, accessibility, price and promotion of foods and beverages, has a significant influence on oral health through food consumption. With this systematic literature review, we systematically summarize the available evidence on relations between the food environment and oral health outcomes in children and adults. Methods English-language studies were identified through a systematic literature search, executed by a medical information specialist, on OVID/Medline, Embase, Web of Science and CINAHL. Title and abstract screening, full-text screening and quality assessment [using the Quality Assessment with Diverse Studies (QuADS) tool] were done independently by two authors. Results Twenty-three studies were included, of which 1 studied the consumer food environment (food labeling), 3 the community food environment (e.g. number of food stores in the community), 5 the organizational food environment (availability of healthy foods and beverages in schools), 2 the information environment (television advertisements) and 13 government and industry policies related to the food environment (e.g. implementation of a sugar-sweetened beverage tax). Almost all studies found that unhealthy food and beverage environments had adverse effects on oral health, and that policies improving the healthiness of food and beverage environments improved—or would improve in case of a modeling study—oral health. Conclusions This systematic literature review provides evidence, although of low to moderate quality and available in a low quantity only, that several aspects of the food environment, especially policies affecting the food environment, are associated with oral health outcomes.

Introduction: Patients participating in randomized controlled trials (RCTs) are susceptible to a wide range of different adverse events (AE) during the RCT. MedDRA® is a hierarchical standardization terminology to structure the AEs reported in an RCT. The lowest level in the MedDRA hierarchy is a single medical event, and every higher level is the aggregation of the lower levels. Method: We propose a multi-stage Bayesian hierarchical Poisson model for estimating MedDRA-coded AE rate ratios (RRs). To deal with rare AEs, we introduce data aggregation at a higher level within the MedDRA structure and based on thresholds on incidence and MedDRA structure. Results: With simulations, we showed the effects of this data aggregation process and the method's performance. Furthermore, an application to a real example is provided and compared with other methods. Conclusion: We showed the benefit of using the full MedDRA structure and using aggregated data. The proposed model, as well as the pre-processing, is implemented in an R-package: BAHAMA.

Introduction The Olerud Molander Ankle Score (OMAS) is a widely used validated Patient Reported Outcome Measure (PROM). For clinical research, it is important to determine the Minimal Clinically Important Difference (MCID). The objective of this study was to determine the MCID of the OMAS at several moments in the follow-up, in a cohort of patients that underwent open reduction and internal fixation of unstable ankle fractures with syndesmotic injury. Materials and methods Data for this descriptive study were extracted from a prospective randomized controlled trial, the RODEO trial. The Dutch version of the OMAS was completed at 3, 6 and 12-month follow-up and estimated at baseline. The used anchor-based methods were: mean change and ROC curve. The distribution-based methods were: 0.5SD and minimal detectable change (MDC). Results This cohort included 148 patients. The mean OMAS score in the group with minimal improvement between 3 and 6 months was 15.0 (SD 17.5, 95%CI 9.4–20.6) and between 6 and 12 months 9.5 (SD 17.1, 95% CI 3.1–15.9). The ROC curve between 3 and 6 months resulted in a MCID of 12.5 (AUC 0.72) and between 6 and 12 months, the MCID was 7.5 (AUC 0.78). Using 0.5 SD, the MCID was 10.52 (SD 21.04) at 3 months, 11.37 (SD 22.73) at 6 months and 10.47 (SD 20.94) at 12 months. The MDC was 4.72 at 3 months, 5.20 at 6 months and 4.71 at 12 months. Conclusions The calculated MCID in patients following surgery for unstable ankle fractures ranges from 10.5 to 15.0 at 3–6-month follow-up and from 7.5 to 11.4 at 6–12-month follow-up, depending on moment and method.

Contains fulltext : 249039.pdf (Publisher’s version ) (Open Access) Stress initiates a cascade of (neuro)biological, physiological, and behavioral changes, allowing us to respond to a challenging environment. The human response to acute stress can be studied in detail in controlled settings, usually in a laboratory environment. To this end, many studies employ acute stress paradigms to probe stress-related outcomes in healthy and patient populations. Though valuable, these studies in themselves often have relatively limited sample sizes. We established a data-sharing and collaborative interdisciplinary initiative, the STRESS-NL database, which combines (neuro)biological, physiological, and behavioral data across many acute stress studies in order to accelerate our understanding of the human acute stress response in health and disease (www.stressdatabase.eu). Researchers in the stress field from 12 Dutch research groups of 6 Dutch universities created a database to achieve an accurate inventory of (neuro)biological, physiological, and behavioral data from laboratory-based human studies that used acute stress tests. Currently, the STRESS-NL database consists of information on 5529 individual participants (2281 females and 3348 males, age range 6-99 years, mean age 27.7 ± 16 years) stemming from 57 experiments described in 42 independent studies. Studies often did not use the same stress paradigm; outcomes were different and measured at different time points. All studies currently included in the database assessed cortisol levels before, during and after experimental stress, but cortisol measurement will not be a strict requirement for future study inclusion. Here, we report on the creation of the STRESS-NL database and infrastructure to illustrate the potential of accumulating and combining existing data to allow meta-analytical, proof-of-principle analyses. The STRESS-NL database creates a framework that enables human stress research to take new avenues in explorative and hypothesis-driven data analyses with high statistical power. Future steps could be to incorporate new studies beyond the borders of the Netherlands; or build similar databases for experimental stress studies in rodents. In our view, there are major scientific benefits in initiating and maintaining such international efforts. 9 p.

Background: Glioblastoma patients are considered to be at high risk of venous thromboembolism (VTE) and major bleeding (MB), although reliable incidence estimates are lacking. Moreover, the risk of arterial thromboembolism (ATE) in these patients is largely unknown. Our aim was to assess the cumulative incidence, predictors, and prognostic impact of VTE, ATE, and MB on subsequent complications and mortality. Methods: Cohort study of 967 consecutive patients diagnosed with glioblastoma between 2004–2020 in two hospitals. Patients were followed from 6 months before date of histopathological glioblastoma diagnosis up to 2 years after, or until an outcome of interest (VTE, ATE, and MB) or death occurred, depending on the analysis. Cumulative incidences were estimated with death as competing risk. Cox regression was used to identify predictors and the prognostic impact. Results: A total of 101 patients were diagnosed with VTE, 50 with ATE, and 126 with MB during a median follow-up of 15 months (interquartile range 9.0–22). The adjusted 1-year cumulative incidence of VTE was 7.5% (95% confidence interval [CI] 5.9–9.3), of ATE 4.1% (95% CI 3.0–5.6), and of MB 12% (95% CI 9.6–14). Older age, type of surgery, and performance status were predictors of VTE. Incident VTE during follow-up was associated with MB (adjusted HR 4.7, 95% CI 2.5–9.0). MB and VTE were associated with mortality (adjusted HR 1.7, 95% CI 1.3–2.1 and 1.3, 95% CI 1.0–1.7, respectively). Conclusion: We found considerable incidences of VTE and MB in glioblastoma patients, with both complications associated with poorer prognosis. Our observations emphasize the need for prospective studies to determine optimal thromboprophylaxis and VTE treatment strategy in these patients.

Background: This study aimed to examine the associations of plasma superoxide dismutase (SOD) activity, an indicator of oxidative stress, with disability in activities of daily living (ADL) and objective physical functioning among Chinese older adults. Methods: We used cross-sectional data of 2223 older adults (≥65 years, including 1505 adults≥80 years) from the 2011/2012 main survey of the Chinese Longitudinal Healthy Longevity Survey (CLHLS) and the 2012 biomarker sub-study. Plasma SOD activity was assessed by the T-SOD assay kit based on the hydroxylamine method. Outcomes included ADL disability and disability in three objective physical tasks (standing up from a chair, picking up a book from the floor, and turning around 360°). Logistic regression models were used to examine the associations of plasma SOD activity with outcomes. Results: After controlling for age and sex, compared with participants in the lowest quartile group of SOD activity, those in the highest quartile group had 31% lower odds of ADL disability (odds ratio [OR]: 0.69; 95%CI: 0.48, 0.98); 60% lower odds of disability in standing up from a chair (OR: 0.40; 95%CI: 0.25, 0.63); and 57% lower odds of disability in picking up a book from a floor (OR: 0.43; 95%CI: 0.28, 0.65). The results did not change substantially after controlling for additional covariates. We did not observe statistically significant age and sex differences. Conclusions: Overall, plasma SOD activity was associated with subjectively and objectively measured disability in Chinese older adults, highlighting the potential of SOD activity to serve as a biomarker of physical functioning.

Objectives: To describe divergence between actionable statements issued by coronavirus disease 2019 (COVID-19) guideline developers cataloged on the “COVID-19 Recommendations and Gateway to Contextualization” platform. Study Design and Setting: We defined divergence as at least two comparable actionable statements with different explicit judgments of strength, direction, or subgroup consideration of the population or intervention. We applied a content analysis to compare guideline development methods for a sample of diverging statements and to evaluate factors associated with divergence. Results: Of the 138 guidelines evaluated, 85 (62%) contained at least one statement that diverged from another guideline. We identified 223 diverging statements in these 85 guidelines. We grouped statements into 66 clusters. Each cluster addressed the same population, intervention, and comparator group or just similar interventions. Clinical practice statements were more likely to diverge in an explicit judgment of strength or direction compared to public health statements. Statements were more likely to diverge in strength than direction. The date of publication, used evidence, interpretation of evidence, and contextualization considerations were associated with divergence. Conclusion: More than half of the assessed guidelines issued at least one diverging statement. This study helps in understanding the types of differences between guidelines issuing comparable statements and factors associated with their divergence. © 2022

Background: The true influence of body mass index on the outcome of esophageal cancer surgery is unclear. The aim of this study was to determine the relation between preoperative body mass index and clinical and oncological outcomes of esophagectomy for cancer in a patient cohort from the Dutch nationwide audit. Methods: All patients who underwent esophagectomy for cancer between January 2011 and 2016 were identified in the Dutch Upper Gastrointestinal Cancer Audit. Patients were divided into 4 body mass index categories (2 underweight, 18.5 to 25 kg/m 2 normal weight, 25 to 30 kg/m 2 overweight, and >30 kg/m 2 obese) and were compared for clinical and oncological outcomes with the use of propensity score–matched analysis. Results: Of the patients, 2,598 were included (underweight = 70, normal weight = 1,097, overweight = 1,007, and obese = 424). Before propensity score–matched analysis, underweight patients had a significantly longer hospital stay, more chyle leakage, underwent more re-operations, and had a higher in-hospital/30-day mortality compared to the other weight groups. After propensity score–matched analysis, 560 patients were included: 62 were underweight, 180 were normal weight, 165 were overweight, and 153 were obese. Length of hospital stay, chyle leakage, necrosis of the reconstruction, re-interventions, re-operations, re-admittance to the intensive care unit/medium care unit, and in-hospital/30-day mortality were seen most in the underweight group. No differences were seen in intraoperative complications and oncological outcomes. Conclusion: Underweight patients are more prone for the development of postoperative complications after esophagectomy. Physicians and dieticians should be aware of the impact of underweight on postoperative outcome. Future studies should focus on nutritional status and the effect of preoperative correction of body weight.

Background: Improving maternal lifestyle before conception may prevent the adverse effects of maternal obesity on their children’s future cardiovascular disease (CVD) risk. In the current study, we examined whether a preconception lifestyle intervention in women with obesity could alter echocardiographic indices of cardiovascular health in their children. Methods: Six years after a randomized controlled trial comparing the effects of a 6-month preconception lifestyle intervention in women with obesity and infertility prior to fertility care to prompt fertility care, 315 of the 341 children conceived within 24 months after randomization were eligible for this study. The intervention was aimed at weight loss (≥5% or until BMI < 29 kg/m 2). Children underwent echocardiographic assessment of cardiac structure and function, conducted by a single pediatric cardiologist, blinded to group allocation. Results were adjusted for multiple variables including body surface area, age, and sex in linear regression analyses. Results: Sixty children (32 girls, 53%) were included, mean age 6.5 years (SD 1.09). Twenty-four children (40%) were born to mothers in the intervention group. Children of mothers from the intervention group had a lower end-diastolic interventricular septum thickness (−0.88 Z-score, 95%CI −1.18 to −0.58), a lower left ventricle mass index (−8.56 g/m 2, 95%CI −13.09 to −4.03), and higher peak systolic and early diastolic annular velocity of the left ventricle (1.43 cm/s 95%CI 0.65 to 2.20 and 2.39 cm/s 95%CI 0.68 to 4.11, respectively) compared to children of mothers from the control group. Conclusions: Children of women with obesity, who underwent a preconception lifestyle intervention, had improved cardiac structure and function; a thinner interventricular septum, lower left ventricle mass, and improved systolic and diastolic tissue Doppler velocities. Despite its high attrition rates, our study provides the first experimental human evidence suggesting that preconception lifestyle interventions may present a method of reducing CVD risk in the next generation. Clinical trial registration: LIFEstyle study: Netherlands Trial Register: NTR1530 (https://www.trialregister.nl/trial/1461). This follow-up study was approved by the medical ethics committee of the University Medical Centre Groningen (METC code: 2008/284).

This cross-sectional study evaluates the existence and timing of trial registration for randomized clinical trials (RCTs) published from 2002 to 2017 as well as substantive changes to the primary outcomes entered into registry information after those studies started.

Background & Aims: Patients with primary sclerosing cholangitis (PSC) may suffer from complaints such as pruritus, right upper abdominal quadrant pain (RUQ-A) and fatigue. However, the severity of these complaints, daily and/or seasonal patterns and other factors of influence in PSC are largely unknown. The aim of this study is to assess daily symptoms and patterns thereof in PSC patients in their natural setting. Methods: A mobile application was designed according to the experience sampling method. Push notifications with a response time of max 4 h were sent during tiers of 3 months. Questions comprised VAS scales on degree of pruritus, fatigue, RUQ-A, time of the day these symptoms were worst, as well as time of intake of medication. Linear mixed modelling was used to identify patient- and external factors associated with pruritus, fatigue and RUQ-A pain. Results: A total of 6713 questionnaires were completed by 137 patients. Fatigue was the most prevalent symptom among PSC patients being reported in a striking 71% of measurements, followed by pruritus (38%). Both increased during the day and were associated with longer disease duration. A highly significant correlation between pruritus and day temperature was observed (ρ = −0.14, p =.000), and itch was generally worse during winter (p =.000). Patient preference for the tool was high. Conclusion: Pruritus and fatigue are prevalent symptoms in the daily life of PSC patients and show a distinct diurnal pattern. This may have implications for efficient dosing of anti-pruritic agents. The level of pruritus is highly correlated with day temperature, which may have several implications.

Aims ST-depression and T-wave inversion are frequently present on the post-resuscitation electrocardiogram (ECG). However, the prognostic value of ischaemic ECG patterns is unknown. Methods and results In this post-hoc subgroup analysis of the Coronary Angiography after Cardiac arrest (COACT) trial, the first in-hospital post-resuscitation ECG in out-of-hospital cardiac arrest patients with a shockable rhythm was analysed for ischaemic ECG patterns. Ischaemia was defined as ST-depression of ≥0.1 mV, T-wave inversion in ≥2 contiguous leads, or both. The primary endpoint was 90-day survival. Secondary endpoints were rate of acute unstable lesions, levels of serum troponin-T, and left ventricular function. Of the 510 out-of-hospital cardiac arrest patients, 340 (66.7%) patients had ischaemic ECG patterns. Patients with ischaemic ECG patterns had a worse 90-day survival compared with those without [hazard ratio 1.51; 95% confidence interval (CI) 1.08–2.12; P = 0.02]. A higher sum of ST-depression was associated with lower survival (log-rank = 0.01). The rate of acute unstable lesions (14.5 vs. 15.8%; odds ratio 0.90; 95% CI 0.51–1.59) did not differ between the groups. In patients with ischaemic ECG patterns, maximum levels of serum troponin-T (μg/L) were higher [0.595 (interquartile range 0.243–1.430) vs. 0.359 (0.159–0.845); ratio of geometric means 1.58; 1.13–2.20] and left ventricular function (%) was worse (44.7 ± 12.5 vs. 49.9 ± 13.3; mean difference −5.13; 95% CI −8.84 to −1.42). Adjusted for age and time to return of spontaneous circulation, ischaemic ECG patterns were no longer associated with survival. Conclusion Post-arrest ischaemic ECG patterns were associated with worse 90-day survival. A higher sum of ST-depression was associated with lower survival. Adjusted for age and time to return of spontaneous circulation, ischaemic ECG patterns were no longer associated with survival.

Contains fulltext : 287686.pdf (Publisher’s version ) (Open Access) OBJECTIVE: To determine the prevalence of depression, anxiety, and posttraumatic stress disorder (PTSD) years after hyperemesis gravidarum (HG) and its association with HG severity. MATERIAL AND METHODS: This prospective cohort study consisted of a follow-up of 215 women admitted for HG, who were eligible to participate in a randomized controlled trial and either declined or agreed to be randomized between 2013 and 2016 in 19 hospitals in the Netherlands. Participants completed the Hospital Anxiety and Depression Scale (HADS) six weeks postpartum and during follow-up and the PTSD checklist for DSM-5 (PCL-5) during follow-up. An anxiety or depression score ≥8 is indicative of an anxiety or depression disorder and a PCL-5 ≥ 31 indicative of PTSD. Measures of HG severity were symptom severity (PUQE-24: Pregnancy Unique Quantification of Emesis), weight change, duration of admissions, readmissions, and admissions after the first trimester. RESULTS: About 54/215 participants completed the HADS six weeks postpartum and 73/215 participants completed the follow-up questionnaire, on average 4.5 years later. Six weeks postpartum, 13 participants (24.1%) had an anxiety score ≥8 and 11 participants (20.4%) a depression score ≥8. During follow-up, 29 participants (39.7%) had an anxiety score ≥8, 20 participants (27.4%) a depression score ≥8, and 16 participants (21.9%) a PCL-5 ≥ 31.Multivariable logistic regression analysis showed that for every additional point of the mean PUQE-24 three weeks after inclusion, the likelihood of having an anxiety score ≥8 and PCL-5 ≥ 31 at follow-up increased with OR 1.41 (95% CI: 1.10;1.79) and OR 1.49 (95% CI: 1.06;2.10) respectively. CONCLUSION: Depression, anxiety, and PTSD symptoms are common years after HG occurred.

Background High-grade squamous intraepithelial lesions (HSIL) or cervical intraepithelial neoplasia (CIN) grade 2/3 lesions in human papillomavirus (HPV)–positive women 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 ( Conclusions Compared with HPV16/18 genotyping, the FAM19A4/miR124-2 methylation test detects nonproductive, transforming CIN2/3 lesions with high specificity in women aged

Background We have developed a model of stratified exercise therapy that distinguishes three knee osteoarthritis (OA) subgroups (‘high muscle strength subgroup’, ‘low muscle strength subgroup’, ‘obesity subgroup’), which are provided subgroup-specific exercise therapy (supplemented by a dietary intervention for the ‘obesity subgroup’). In a large clinical trial, this intervention was found to be no more effective than usual exercise therapy. The present qualitative study aimed to explore experiences from users of this intervention, in order to identify possible improvements. Methods Qualitative research design embedded within a cluster randomized controlled trial in a primary care setting. A random sample from the experimental arm (i.e., 15 patients, 11 physiotherapists and 5 dieticians) was interviewed on their experiences with receiving or applying the intervention. Qualitative data from these semi-structured interviews were thematically analysed. Results We identified four themes: one theme regarding the positive experiences with the intervention and three themes regarding perceived barriers. Although users from all 3 perspectives (patients, physiotherapists and dieticians) generally perceived the intervention as having added value, we also identified several barriers, especially for the ‘obesity subgroup’. In this ‘obesity subgroup’, physiotherapists perceived obesity as difficult to address, dieticians reported that more consultations are needed to reach sustainable weight loss and both physiotherapists and dieticians reported a lack of interprofessional collaboration. In the ‘high muscle strength subgroup’, the low number of supervised sessions was perceived as a barrier by some patients and physiotherapists, but as a facilitator by others. A final theme addressed barriers to knee OA treatment in general, with lack of motivation as the most prominent of these. Conclusion Our qualitative study revealed a number of barriers to effective application of the stratified exercise therapy, especially for the ‘obesity subgroup’. Based on these barriers, the intervention and its implementation could possibly be improved. Moreover, these barriers are likely to account at least partly for the lack of superiority over usual exercise therapy. Trial registration The Netherlands National Trial Register (NTR): NL7463 (date of registration: 8 January 2019).

Contains fulltext : 251574.pdf (Publisher’s version ) (Open Access) BACKGROUND: The probability of undergoing treatment with curative intent according to the hospital of diagnosis varies for esophagogastric cancer in the Netherlands. Little is known about the factors contributing to this variation. This study aimed to improve the understanding of the differences between the multidisciplinary team meeting treatment proposal and the treatment that was actually carried out and to qualitatively investigate the differences in treatment decision-making after the multidisciplinary team meeting treatment proposal between hospitals. METHODS: To gain an in-depth understanding of treatment decision-making, quantitative data (i.e., multidisciplinary team meeting proposal and treatment that was carried out) were collected from the Netherlands Cancer Registry. Changes in the multidisciplinary team meeting proposal and applied treatment comprised changes in the type of treatment option (i.e., curative or palliative, or no change) and were calculated according to the multivariable multilevel probability of undergoing treatment with curative intent (low, middle, and high). Qualitative data were collected from eight hospitals, including observations of 26 outpatient clinic consultations, 30 in-depth interviews with clinicians, seven focus groups with clinicians, and three focus groups with patients. Clinicians and patients' perspectives were assessed using thematic content analysis. RESULTS: The multidisciplinary team meeting proposal and applied treatment were concordant in 97% of the cases. Clinicians' implementation of treatment decision-making in clinical practice varied, which was mentioned by the clinicians to be due to the clinician's personality and values. Differences between clinicians consisted of discussing all treatment options versus only the best fitting treatment option and the extent of discussing the benefits and harms. Most patients aimed to undergo curative treatment regardless of the consequences, since they believed this could prolong their life. CONCLUSION: Since changes in the multidisciplinary team meeting-proposed treatment and actual treatment were rarely observed, this study emphasizes the importance of an adequately formulated multidisciplinary team meeting proposal.

Background & Aims: Cardiometabolic diseases (CMDs) have shared properties and causes. Insulin resistance is a risk factor and characteristic of CMDs and has been suggested to be modulated by plasma metabolites derived from gut microbiota (GM). Because diet is among the most important modulators of GM, we performed a systematic review of the literature to assess whether CMDs can be modulated via dietary interventions targeting the GM. Methods: A systematic review of the literature for clinical studies was performed on Ovid MEDLINE and Ovid Embase. Studies were assessed for risk of bias and patterns of intervention effects. A meta-analysis with random effects models was used to evaluate the effect of dietary interventions on clinical outcomes. Results: Our search yielded 4444 unique articles, from which 15 randomized controlled trials and 6 nonrandomized clinical trials were included. The overall risk of bias was high in all studies. In general, most dietary interventions changed the GM composition, but no consistent effect could be found. Results of the meta-analyses showed that only diastolic blood pressure is decreased across interventions compared with controls (mean difference: −3.63 mm Hg; 95% confidence interval, −7.09 to −0.17; I2 = 0%, P = .04) and that a high-fiber diet was associated with reduced triglyceride levels (mean difference: −0.69 mmol/L; 95% confidence interval, −1.36 to −0.02; I2 = 59%, P = .04). Other CMD parameters were not affected. Conclusions: Dietary interventions modulate GM composition, blood pressure, and circulating triglycerides. However, current studies have a high methodological heterogeneity and risk of bias. Well-designed and controlled studies are thus necessary to better understand the complex interaction between diet, microbiome, and CMDs. PROSPERO: CRD42020188405

Core outcome sets are critically important outcomes that should be measured in clinical trials. Their absence in atopic dermatitis is a form of research waste and impedes combining evidence to inform patient care. Here, we articulate the rationale for core outcome sets in atopic dermatitis and review the work of the international Harmonising Outcome Measures for Eczema group from its inception in Munich, 2010. We describe core domain determination (what should be measured), to instrument selection (how domains should be measured), culminating in the complete core outcome measurement set in Tokyo, 2019. Using a "road map," Harmonising Outcome Measures for Eczema includes diverse research methods including Delphi and nominal group techniques informed by systematic reviews of properties of candidate instruments. The 4 domains and recommended instruments for including in all clinical trials of atopic dermatitis are patient symptoms, measured by Patient-Oriented Eczema Measure and peak Numerical Rating Scale 11 for itch intensity over 24 hours, clinical signs measured using the Eczema Area and Severity Index, quality of life measured by the Dermatology Life Quality Index series for adults, children, and infants, and long-term control measured by either Recap of atopic eczema or Atopic Dermatitis Control Tool. Published version Details of funding for each of the consensus meetings is outlined in the published meeting reports. The following additional funding sources contributed to facilitating the HOME COS development: National Institute for Health and Care Research Senior Investigator award to Prof Hywel Williams (RE 2374) funded travel costs to enable UK patients to participate in HOME meetings; National Institute for Health and Care Research Programme Grant for Applied Research RP-PG-0407-10177 ‘‘Setting Priorities and Reducing Uncertainties for the Prevention and Treatment of Skin Disease (SPRUSD)’’ was used to support completion of the some of the systematic reviews, the cost of meetings and patient and public involvement (Prof Kim Thomas); NIH NIAMS A Community-based Assessment of Skin Care, Allergies, and Eczema: The CASCADE Trial grant number 5 R01 AR071057-05 and Oregon Clinical and Translational Research Institute (OCTRI) assisted with outcome evaluations and associated travel costs (Prof Eric Simpson); Laura Howells received a PhD studentship from the British Skin Foundation (Ref: 8016) for studies that informed this work.

Contains fulltext : 251784.pdf (Publisher’s version ) (Closed access) BACKGROUND: Concerns have been raised regarding the risks of SARS-CoV-2 breakthrough infections in vaccinated patients with immune-mediated inflammatory diseases treated with immunosuppressants, but clinical data on breakthrough infections are still scarce. The primary objective of this study was to compare the incidence and severity of SARS-CoV-2 breakthrough infections between patients with immune-mediated inflammatory diseases using immunosuppressants, and controls (patients with immune-mediated inflammatory diseases not taking immunosuppressants and healthy controls) who had received full COVID-19 vaccinations. The secondary objective was to explore determinants of breakthrough infections of the delta (B.1.617.2) variant of SARS-CoV-2, including humoral immune responses after vaccination. METHODS: In this substudy, we pooled data collected in two large ongoing prospective multicentre cohort studies conducted in the Netherlands (Target to-B! [T2B!] study and Amsterdam Rheumatology Center COVID [ARC-COVID] study). Both studies recruited adult patients (age ≥18 years) with immune-mediated inflammatory diseases and healthy controls. We sourced clinical data from standardised electronic case record forms, digital questionnaires, and medical files. We only included individuals who were vaccinated against SARS-CoV-2. For T2B!, participants were recruited between Feb 2 and Aug 1, 2021, and for ARC-COVID, participants were recruited between April 26, 2020, and March 1, 2021. In this study we assessed data on breakthrough infections collected between July 1 and Dec 15, 2021, a period in which the delta SARS-CoV-2 variant was the dominant variant in the Netherlands. We defined a SARS-CoV-2 breakthrough infection as a PCR-confirmed or antigen test-confirmed SARS-CoV-2 infection that occurred at least 14 days after vaccination. All breakthrough infections during this period were assumed to be due to the delta variant due to its dominance during the study period. We analysed post-vaccination serum samples for anti-receptor binding domain (RBD) antibodies to assess the humoral vaccination response (T2B! study only) and anti-nucleocapsid antibodies to identify asymptomatic breakthrough infections (ARC-COVID study only). We used multivariable logistic regression analyses to explore potential clinical and humoral determinants associated with the odds of breakthrough infections. The T2B! study is registered with the Dutch Trial Register, Trial ID NL8900, and the ARC-COVID study is registered with Dutch Trial Register, trial ID NL8513. FINDINGS: We included 3207 patients with immune-mediated inflammatory diseases who receive immunosuppressants, and 1807 controls (985 patients with immune-mediated inflammatory disease not on immunosuppressants and 822 healthy controls). Among patients receiving immunosuppressants, mean age was 53 years (SD 14), 2042 (64%) of 3207 were female and 1165 (36%) were male; among patients not receiving immunosuppressants, mean age was 54 years (SD 14), 598 (61%) of 985 were female and 387 (39%) were male; and among healthy controls, mean age was 57 years (SD 13), 549 (67%) of 822 were female and 273 (33%) were male. The cumulative incidence of PCR-test or antigen-test confirmed SARS-CoV-2 breakthrough infections was similar in patients on immunosuppressants (148 of 3207; 4·6% [95% CI 3·9-5·4]), patients not on immunosuppressants (52 of 985; 5·3% [95% CI 4·0-6·9]), and healthy controls (33 of 822; 4·0% [95% CI 2·8-5·6]). There was no difference in the odds of breakthrough infection for patients with immune-mediate inflammatory disease on immunosuppressants versus combined controls (ie, patients not on immunosuppressants and healthy controls; adjusted odds ratio 0·88 [95% CI 0·66-1·18]). Seroconversion after vaccination (odds ratio 0·58 [95% CI 0·34-0·98]; T2B! cohort only) and SARS-CoV-2 infection before vaccination (0·34 [0·18-0·56]) were associated with a lower odds of breakthrough infections. INTERPRETATION: The incidence and severity of SARS-CoV-2 breakthrough infections in patients with immune-mediated inflammatory diseases on immunosuppressants was similar to that in controls. However, caution might still be warranted for those on anti-CD20 therapy and those with traditional risk factors. FUNDING: ZonMw (the Netherlands Organization for Health Research and Development) and Reade foundation.

Background Silent paroxysmal atrial fibrillation (AF) may be difficult to diagnose, and AF burden is hard to establish. In contrast to conventional diagnostic devices, photoplethysmography (PPG)–driven smartwatches or wristbands allow for long-term continuous heart rhythm assessment. However, most smartwatches lack an integrated PPG-AF algorithm. Adding a standalone PPG-AF algorithm to these wrist devices might open new possibilities for AF screening and burden assessment. Objective The aim of this study was to assess the accuracy of a well-known standalone PPG-AF detection algorithm added to a popular wristband and smartwatch, with regard to discriminating AF and sinus rhythm, in a group of patients with AF before and after cardioversion (CV). Methods Consecutive consenting patients with AF admitted for CV in a large academic hospital in Amsterdam, the Netherlands, were asked to wear a Biostrap wristband or Fitbit Ionic smartwatch with Fibricheck algorithm add-on surrounding the procedure. A set of 1-min PPG measurements and 12-lead reference electrocardiograms was obtained before and after CV. Rhythm assessment by the PPG device-software combination was compared with the 12-lead electrocardiogram. Results A total of 78 patients were included in the Biostrap-Fibricheck cohort (156 measurement sets) and 73 patients in the Fitbit-Fibricheck cohort (143 measurement sets). Of the measurement sets, 19/156 (12%) and 7/143 (5%), respectively, were not classifiable by the PPG algorithm due to bad quality. The diagnostic performance in terms of sensitivity, specificity, positive predictive value, negative predictive value, and accuracy was 98%, 96%, 96%, 99%, 97%, and 97%, 100%, 100%, 97%, and 99%, respectively, at an AF prevalence of ~50%. Conclusions This study demonstrates that the addition of a well-known standalone PPG-AF detection algorithm to a popular PPG smartwatch and wristband without integrated algorithm yields a high accuracy for the detection of AF, with an acceptable unclassifiable rate, in a semicontrolled environment.

Researchers have proposed that the minimal important difference (MID), the smallest change or difference that patients perceive as important, could aid the interpretation of patient reported outcomes measure (PROM) scores. When multiple MIDs for a given PROM differ substantially, the selection of an optimal MID to aid interpretation could prove challenging. This article describes a systematic, step-by-step selection approach developed to resolve this problem. An optimal MID, at least, should be methodologically sound and should, as far as possible, match the intended application contexts. Therefore, this approach is geared to explaining the variability of the MIDs for the PROM of interest by the methodological rigor and contextualised factors influencing the MID application, and where appropriate, provides one optimal MID (ie, the median of the selected estimates in a relatively narrow range).

Aims and Objectives: Studies in adult medicine have shown that physicians base testing decisions on the patient's clinical condition but also consider other factors, including local practice or patient expectations. In pediatrics, physicians and parents jointly decide on behalf of a (young) child. This might demand more explicit and more complex deliberations, with sometimes conflicting interests. We explored pediatricians' considerations in diagnostic test ordering and the factors that influence their deliberation. Method: We performed in-depth, semistructured interviews with a purposively selected heterogeneous sample of 20 Dutch pediatricians. We analyzed transcribed interviews inductively using a constant comparative approach, and clustered data across interviews to derive common themes. Results: Pediatricians perceived test-related burden in children higher compared with adults, and reported that avoiding an unjustified burden causes them to be more restrictive and deliberate in test ordering. They felt conflicted when parents desired testing or when guidelines recommended diagnostic tests pediatricians perceived as unnecessary. When parents demanded testing, they would explore parental concern, educate parents about harms and alternative explanations of symptoms, and advocate watchful waiting. Yet they reported sometimes performing tests to appease parents or to comply with guidelines, because of feared personal consequences in the case of adverse outcomes. Conclusion: We obtained an overview of the considerations that are weighed in pediatric test decisions. The comparatively strong focus on prevention of harm motivates pediatricians to critically appraise the added value of testing and drivers of low-value testing. Pediatricians' relatively restrictive approach to testing could provide an example for other disciplines. Improved guidelines and physician and patient education could help to withstand the perceived pressure to test.

Human microbiome research is helped by the characterization of microbial networks, as these may reveal key microbes that can be targeted for beneficial health effects. Prevailing methods of microbial network characterization are based on measures of association, often applied to limited sampling points in time. Here, we demonstrate the potential of wavelet clustering, a technique that clusters time series based on similarities in their spectral characteristics. We illustrate this technique with synthetic time series and apply wavelet clustering to densely sampled human gut microbiome time series. We compare our results with hierarchical clustering based on temporal correlations in abundance, within and across individuals, and show that the cluster trees obtained by using either method are significantly different in terms of elements clustered together, branching structure and total branch length. By capitalizing on the dynamic nature of the human microbiome, wavelet clustering reveals community structures that remain obscured in correlation-based methods.

Patients with MYC rearranged (MYC-R) diffuse large B-cell lymphoma (DLBCL) have a poor prognosis. Previously, we demonstrated in a single-arm phase II trial (HOVON-130) that addition of lenalidomide to R-CHOP (R2CHOP) is well-tolerated and yields similar complete metabolic remission rates as more intensive chemotherapy regimens in literature. In parallel with this single-arm interventional trial, a prospective observational screening cohort (HOVON-900) was open in which we identified all newly diagnosed MYC-R DLBCL patients in the Netherlands. Eligible patients from the observational cohort that were not included in the interventional trial served as control group in the present risk-adjusted comparison. R2CHOP treated patients from the interventional trial (n = 77) were younger than patients in the R-CHOP control cohort (n = 56) (median age 63 versus 70 years, p = 0.018) and they were more likely to have a lower WHO performance score (p = 0.013). We adjusted for differences at baseline using 1:1 matching, multivariable analysis, and weighting using the propensity score to reduce treatment-selection bias. These analyses consistently showed improved outcome after R2CHOP with HRs of 0.53, 0.51, and 0.59, respectively, for OS, and 0.53, 0.59, and 0.60 for PFS. Thus, this non-randomized risk-adjusted comparison supports R2CHOP as an additional treatment option for MYC-R DLBCL patients.

Artificial intelligence (AI) based algorithms for classification of suspicious skin lesions have been implemented in mobile phone apps (mHealth), but their effect on healthcare systems is undocumented. In 2019, a large Dutch health insurance company offered 2.2 million adults free access to an mHealth app for skin cancer detection. To study the impact on dermatological healthcare consumption, we conducted a retrospective population-based pragmatic study. We matched 18,960 mHealth-users who completed at least one successful assessment with the app to 56,880 controls who did not use the app and calculated odds ratios (OR) to compare dermatological claims between both groups in the first year after granting free access. A short-term cost-effectiveness analysis was performed to determine the cost per additional detected (pre)malignancy. Here we report that mHealth-users had more claims for (pre)malignant skin lesions than controls (6.0% vs 4.6%, OR 1.3 (95% CI 1.2–1.4)) and also a more than threefold higher risk of claims for benign skin tumors and nevi (5.9% vs 1.7%, OR 3.7 (95% CI 3.4–4.1)). The costs of detecting one additional (pre)malignant skin lesion with the app compared to the current standard of care were €2567. Based on these results, AI in mHealth appears to have a positive impact on detecting more cutaneous (pre)malignancies, but this should be balanced against the for now stronger increase in care consumption for benign skin tumors and nevi.

Background Compared with adults with normal glucose metabolism, those with prediabetes tend to be frail. However, it remains poorly understood whether frailty could identify adults who are most at risk of adverse outcomes related to prediabetes. Objective We aimed to systematically evaluate the associations between frailty, a simple health indicator, and risks of multiple adverse outcomes including incident type 2 diabetes mellitus (T2DM), diabetes-related microvascular disease, cardiovascular disease (CVD), chronic kidney disease (CKD), eye disease, dementia, depression, and all-cause mortality in late life among middle-aged adults with prediabetes. Methods We evaluated 38,950 adults aged 40 years to 64 years with prediabetes using the baseline survey from the UK Biobank. Frailty was assessed using the frailty phenotype (FP; range 0-5), and participants were grouped into nonfrail (FP=0), prefrail (1≤FP≤2), and frail (FP≥3). Multiple adverse outcomes (ie, T2DM, diabetes-related microvascular disease, CVD, CKD, eye disease, dementia, depression, and all-cause mortality) were ascertained during a median follow-up of 12 years. Cox proportional hazards regression models were used to estimate the associations. Several sensitivity analyses were performed to test the robustness of the results. Results At baseline, 49.1% (19,122/38,950) and 5.9% (2289/38,950) of adults with prediabetes were identified as prefrail and frail, respectively. Both prefrailty and frailty were associated with higher risks of multiple adverse outcomes in adults with prediabetes (P for trend Conclusions In UK Biobank participants with prediabetes, both prefrailty and frailty are significantly associated with higher risks of multiple adverse outcomes, including T2DM, diabetes-related diseases, and all-cause mortality. Our findings suggest that frailty assessment should be incorporated into routine care for middle-aged adults with prediabetes, to improve the allocation of health care resources and reduce diabetes-related burden.

© 2023 European Alzheimer’s & Dementia Biobank Mendelian Randomization (EADB-MR) Collaboration. JAMA Network Open. Open Access: This is an open access article distributed under the terms of the CC-BY License, Importance: An estimated 40% of dementia is potentially preventable by modifying 12 risk factors throughout the life course. However, robust evidence for most of these risk factors is lacking. Effective interventions should target risk factors in the causal pathway to dementia. Objective: To comprehensively disentangle potentially causal aspects of modifiable risk factors for Alzheimer disease (AD) to inspire new drug targeting and improved prevention. Design, setting, and participants: This genetic association study was conducted using 2-sample univariable and multivariable mendelian randomization. Independent genetic variants associated with modifiable risk factors were selected as instrumental variables from genomic consortia. Outcome data for AD were obtained from the European Alzheimer & Dementia Biobank (EADB), generated on August 31, 2021. Main analyses were conducted using the EADB clinically diagnosed end point data. All analyses were performed between April 12 and October 27, 2022. Exposures: Genetically determined modifiable risk factors. Main outcomes and measures: Odds ratios (ORs) and 95% CIs for AD were calculated per 1-unit change of genetically determined risk factors. Results: The EADB-diagnosed cohort included 39 106 participants with clinically diagnosed AD and 401 577 control participants without AD. The mean age ranged from 72 to 83 years for participants with AD and 51 to 80 years for control participants. Among participants with AD, 54% to 75% were female, and among control participants, 48% to 60% were female. Genetically determined high-density lipoprotein (HDL) cholesterol concentrations were associated with increased odds of AD (OR per 1-SD increase, 1.10 [95% CI, 1.05-1.16]). Genetically determined high systolic blood pressure was associated with increased risk of AD after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.22 [95% CI, 1.02-1.46]). In a second analysis to minimize bias due to sample overlap, the entire UK Biobank was excluded from the EADB consortium; odds for AD were similar for HDL cholesterol (OR per 1-SD unit increase, 1.08 [95% CI, 1.02-1.15]) and systolic blood pressure after adjusting for diastolic blood pressure (OR per 10-mm Hg increase, 1.23 [95% CI, 1.01-1.50]). Conclusions and relevance: This genetic association study found novel genetic associations between high HDL cholesterol concentrations and high systolic blood pressure with higher risk of AD. These findings may inspire new drug targeting and improved prevention implementation., Dr Frikke-Schmidt was funded by grants from the Lundbeck Foundation (grant No. R278-2018-804), the Danish Heart Foundation, and Innovation Fund Denmark (grant No. 9084-00020B).

Background: Traditional cardiovascular risk indicators only partially explain cardiovascular risks in depressed persons. Depressed persons may exhibit a profile of cardiovascular risk indicators that goes beyond traditional cardiovascular risk indicators, such as symptom severity, insomnia, loneliness and neuroticism, yet research on the added value of these depression-related characteristics in predicting cardiovascular risks of depressed persons is scarce. Methods: Data from N = 1028 depressed Dutch adults without prevalent CVD were derived from two longitudinal depression cohort studies. The outcome was medication-confirmed self-reported CVD. Fifteen depression-related clinical and psychological characteristics were included and tested against traditional cardiovascular risk indicators. Data were analysed using Cox regression models. Incremental values of these characteristics were calculated using c-statistics. Results: After a median follow-up of 65.3 months, 12.7% of the participants developed CVD. Only anxiety and depressive symptom severity were associated with incident CVD beyond traditional cardiovascular risk indicators. The c-statistic of the model with traditional cardiovascular risk indicators was 85.47%. This increased with 0.56 or 0.33 percentage points after inclusion of anxiety or depression severity, respectively. Limitations: Other relevant depression-related characteristics were not available in the datasets used. Conclusion: Anxiety and depressive symptom severity were indicative of an increased cardiovascular risk. Including these as additional risk indicators barely improved the ability to assess cardiovascular risks in depressed persons. Although traditional cardiovascular risk indicators performed well in depressed persons, existing risk prediction algorithms need to be validated in depressed persons.

Background: Evidence regarding health-related quality of life (HRQoL) in patients with steroid-refractory acute graft-versus-host disease (SR-aGvHD) is lacking. Evaluating HRQoL was a secondary objective of the HOVON 113 MSC trial. Here we describe the outcomes of the EQ-5D-5L, EORTC QLQ-C30, and FACT-BMT for all adult patients who completed these questionnaires at baseline (i.e., before the start of treatment; n = 26). Methods: Descriptive statistics were used to describe baseline patient and disease characteristics, EQ-5D dimension scores and values, EQ VAS scores, EORTC QLQ-C30 scale/item and summary scores, and FACT-BMT subscale and total scores. Results: The mean EQ-5D value was 0.36. In total, 96% of the patients reported problems with usual activities, 92% with pain/discomfort, 84% with mobility, 80% with self-care, and 72% with anxiety/depression. The mean EORTC QLQ-C30 summary score was 43.50. Mean scale/item scores ranged from 21.79 to 60.00 for functioning scales, from 39.74 to 75.21 for symptom scales, and from 5.33 to 91.67 for single items. The mean FACT-BMT total score was 75.31. Mean subscale scores ranged from 10.09 for physical well-being to 23.94 for social/family well-being. Conclusion: Our study showed that HRQoL in patients with SR-aGvHD is poor. Improving HRQoL and symptom management in these patients should be a top priority.

OBJECTIVE: This study aimed to investigate the effects of occupational exposures on the risk of a positive COVID-19 test, and whether this differed across pandemic waves. METHODS: Data from 207 034 workers from The Netherlands with test data on COVID-19 from June 2020 until August 2021 were available. Occupational exposure was estimated by using the eight dimensions of a COVID-19 job exposure matrix (JEM). Personal characteristics, household composition and residence area were derived from Statistics Netherlands. A test-negative design was applied in which the risk of a positive test was analyzed in a conditional logit model. RESULTS: All eight dimensions of occupational exposure included in the JEM increased the odds of a positive test for the entire study period and three pandemic waves [OR ranging from 1.09, (95% confidence interval (CI) 1.02–1.17) to 1.77 (95% CI 1.61–1.96)]. Adjusting for a previous positive test and other covariates strongly reduced the odds to be infected, but most dimensions remained at elevated risk. Fully adjusted models showed that contaminated work spaces and face covering were mostly relevant in the first two pandemic waves, whereas income insecurity showed higher odds in the third wave. Several occupations have a higher predicted value for a positive COVID-19 test, with variation over time. Discussion Occupational exposures are associated with a higher risk of a positive test, but variations over time exist in occupations with the highest risks. These findings provide insights for interventions among workers for future pandemic waves of COVID-19 or other respiratory epidemics.

Systematic reviews of diagnostic accuracy studies can provide the best available evidence to inform decisions regarding the use of a diagnostic test. In this guide, the authors provide a practical approach for clinicians to appraise diagnostic accuracy systematic reviews and apply their results to patient care. The first step is to identify an appropriate systematic review with a research question matching the clinical scenario. The user should evaluate the rigor of the review methods to evaluate its credibility (Did the review use clearly defined eligibility criteria, a comprehensive search strategy, structured data collection, risk of bias and applicability appraisal, and appropriate meta-analysis methods?). If the review is credible, the next step is to decide whether the diagnostic performance is adequate for clinical use (Do sensitivity and specificity estimates exceed the threshold that makes them useful in clinical practice? Are these estimates sufficiently precise? Is variability in the estimates of diagnostic accuracy across studies explained?). Diagnostic accuracy systematic reviews that are judged to be credible and provide diagnostic accuracy estimates with sufficient certainty and relevance are the most useful to inform patient care. This review discusses comparative, noncomparative, and emerging approaches to systematic reviews of diagnostic accuracy using a clinical scenario and examples based on recent publications.

The aim of this study is to describe how individuals use different food retailers and how food retail usage varies according to socio-demographic and diet-related characteristics. A cross-sectional survey among Dutch adults (N = 1784) was used. Results from the Two-step cluster analysis indicated that there were five clusters of food retail users. Use of discount supermarkets, organic supermarkets, fast-food outlets, and restaurants contributed to clustering, but use of regular supermarkets, local food shops and whether food retailers were close to home or further from home did not. The clusters included mixed food outlet users, discount supermarket and restaurant users, fast-food and restaurant users, predominant discount supermarket users and supermarkets, fast-food and restaurant users. Participants in each cluster had their own characteristics especially in terms of socio-economic position and diet quality. Future studies need to consider further how food retail selection links physical exposure to the food environment and diet.

Introduction: The quality of scars has become an important outcome of burn care. Objective scar assessment through scar surface area measurement enables quantification of scar formation and evaluation of treatment efficacy. 3D technology has proven valid and reliable but often remains cumbersome, expensive, and time-consuming. 3D technology with depth sensors on mobile devices has become available and might surpass these limitations. This study provides a clinimetric assessment of the validity and reliability of a 3D system with a depth sensor for scar surface area measurement. Methods: A technology involving a depth sensor mounted on a mobile device was used. Images and analyses were made with a custom-made software application. A standardized one-keyframe image capturing procedure was followed. To assess validity, stickers with predefined dimensions (8.01 cm2 – 77.70 cm2) were imaged in a single observer setting on various body parts of healthy volunteers. To assess reliability, hypertrophic scars, keloids, and normotrophic scars were imaged and rated by two observers independently. Data are expressed as mean (+/-SD), Coefficient of Variation (CV), Intraclass Correlation Coefficients (ICC), and Limits of Agreements (LoA). Results: Eighty stickers placed on 20 healthy volunteers showed validity with CV between 0.62%− 1.67% for observer A and 0.75%− 1.19% for observer B. For the reliability study, 69 scars on 36 patients were included. Mean scar surface area ranged from 0.83 cm2 to 155.59 cm2. Mean scar surface area measurement was 13.83 cm2 (SD 23.06) for observer A and 13.59 cm2 (SD 23.31) for observer B. Adjusted interobserver CV for trained observers is estimated as 5.59%, with corresponding LoA = 0 ± 0.15 x mean surface area. Interobserver ICCs were 0.99–1.00. Conclusion: This 3D technology with a depth sensor for measuring scar surface area provides valid and reliable data and thereby surpasses expensive and time-consuming 3D cameras.

Background: Impaired awareness of one’s own functioning is highly common in people with Korsakoff’s syndrome (KS). However, it is currently unclear how awareness relates to impairments in daily functioning and quality of life (QoL). Methods: We assessed how impaired awareness relates to cognitive, behavioral, physical, and social functioning and QoL by applying a network analysis. We used cross-sectional data from 215 patients with KS or other severe alcohol-related cognitive deficits living in Dutch long-term care facilities (LTCFs). Results: Apathy has the most central position in the network. Higher apathy scores relate positively to reduced cognition and to a greater decline in activities of daily living and negatively to social participation and the use of antipsychotic drugs. Impaired awareness is also a central node. It is positively related to a higher perceived QoL, reduced cognition and apathy, and negatively to social participation and length of stay in the LTCF. Mediated through apathy and social participation, impaired awareness is indirectly related to other neuropsychiatric symptoms. Conclusions: Impaired awareness is closely related to other domains of daily functioning and QoL of people with KS or other severe alcohol-related cognitive deficits living in LTCFs. Apathy plays a central role. Network analysis offers interesting insights to evaluate the interconnection of different symptoms and impairments in brain disorders such as KS.

Purpose: Severe traumatic brain injury is a leading cause of mortality and morbidity, and these patients are frequently intubated in the prehospital setting. Cerebral perfusion and intracranial pressure are influenced by the arterial partial pressure of CO 2 and derangements might induce further brain damage. We investigated which lower and upper limits of prehospital end-tidal CO 2 levels are associated with increased mortality in patients with severe traumatic brain injury. Methods: The BRAIN-PROTECT study is an observational multicenter study. Patients with severe traumatic brain injury, treated by Dutch Helicopter Emergency Medical Services between February 2012 and December 2017, were included. Follow-up continued for 1 year after inclusion. End-tidal CO 2 levels were measured during prehospital care and their association with 30-day mortality was analyzed with multivariable logistic regression. Results: A total of 1776 patients were eligible for analysis. An L-shaped association between end-tidal CO 2 levels and 30-day mortality was observed (p = 0.01), with a sharp increase in mortality with values below 35 mmHg. End-tidal CO 2 values between 35 and 45 mmHg were associated with better survival rates compared to < 35 mmHg. No association between hypercapnia and mortality was observed. The odds ratio for the association between hypocapnia (< 35 mmHg) and mortality was 1.89 (95% CI 1.53–2.34, p < 0.001) and for hypercapnia (≥ 45 mmHg) 0.83 (0.62–1.11, p = 0.212). Conclusion: A safe zone of 35–45 mmHg for end-tidal CO 2 guidance seems reasonable during prehospital care. Particularly, end-tidal partial pressures of less than 35 mmHg were associated with a significantly increased mortality.