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This study compares actual evapotranspiration (ETa) measurements by a set of six weighable lysimeters, ETa estimates obtained with the eddy covariance (EC) method, and evapotranspiration calculated with the full-form Penman–Monteith equation (ETPM) for the Rollesbroich site in the Eifel (western Germany). The comparison of ETa measured by EC (including correction of the energy balance deficit) and by lysimeters is rarely reported in the literature and allows more insight into the performance of both methods. An evaluation of ETa for the two methods for the year 2012 shows a good agreement with a total difference of 3.8% (19 mm) between the ETa estimates. The highest agreement and smallest relative differences (< 8%) on a monthly basis between both methods are found in summer. ETa was close to ETPM, indicating that ET was energy limited and not limited by water availability. ETa differences between lysimeter and EC were mainly related to differences in grass height caused by harvest and the EC footprint. The lysimeter data were also used to estimate precipitation amounts in combination with a filter algorithm for the high-precision lysimeters recently introduced by Peters et al. (2014). The estimated precipitation amounts from the lysimeter data differ significantly from precipitation amounts recorded with a standard rain gauge at the Rollesbroich test site. For the complete year 2012 the lysimeter records show a 16 % higher precipitation amount than the tipping bucket. After a correction of the tipping bucket measurements by the method of Richter (1995) this amount was reduced to 3%. With the help of an on-site camera the precipitation measurements of the lysimeters were analyzed in more detail. It was found that the lysimeters record more precipitation than the tipping bucket, in part related to the detection of rime and dew, which contribute 17% to the yearly difference between both methods. In addition, fog and drizzle explain an additional 5.5% of the total difference. Larger differences are also recorded for snow and sleet situations. During snowfall, the tipping bucket device underestimated precipitation severely, and these situations contributed also 7.9% to the total difference. However, 36% of the total yearly difference was associated with snow cover without apparent snowfall, and under these conditions snow bridges and snow drift seem to explain the strong overestimation of precipitation by the lysimeter. The remaining precipitation difference (about 33%) could not be explained and did not show a clear relation to wind speed. The variation of the individual lysimeters devices compared to the lysimeter mean are small, showing variations up to 3% for precipitation and 8% for evapotranspiration.

Abstract Background Health care costs are rising due to increasing cancer incidence and the expanding use of high-cost anticancer medicines. Early treatment discontinuation (ETD) may signal inefficiencies in medicine use or reflect appropriate or inevitable clinical decisions. Despite its clinical and economic relevance, national-level data on ETD remain limited. This study aims to quantify ETD rates and associated costs for the highest budget anticancer medicines in the Netherlands and assess trends from 2018 to 2022. Methods We performed a retrospective analysis using real-world data from the Dutch national claims database. ETD was defined as treatment discontinued within 90 days. The study focused on the 30 highest-budget impact anticancer medicines in 2022, assessing ETD rates, related medicine costs, and trends over 5 years (2018-2022). Results In 2022, these medicines accounted for €783 million in expenditures, with ETD representing 9.9% (€77 million). Among 30 343 treatments, 29.7% (9025) were discontinued within 90 days. From 2018 to 2022, total medication costs increased by 27.1%, while ETD costs rose by 9.6%. ETDs increased from 7287 to 9025 (+23.9%), with substantial variation among medicines. For most medicines, survivors accounted for most ETD spending, while ETD followed by death remained 9%. Conclusions Approximately 30% of anticancer treatments are discontinued early, accounting for nearly 10% of medicine costs. While ETD highlights opportunities to improve efficiency, it also includes clinically justified and unavoidable discontinuations. Efforts to reduce avoidable ETD through improved patient selection, toxicity prediction, and treatment optimization are essential for more rational and equitable use of high-cost anticancer therapies.

The use of eddy covariance (EC) CO2 flux measurements in data assimilation and other applications requires an estimate of the random uncertainty. In previous studies, the (classical) two-tower approach has yielded robust uncertainty estimates, but care must be taken to meet the often competing requirements of statistical independence (non-overlapping footprints) and ecosystem homogeneity when choosing an appropriate tower distance. The role of the tower distance was investigated with help of a roving station separated between 8 m and 34 km from a permanent EC grassland station. Random uncertainty was estimated for five separation distances with the classical two-tower approach and an extended approach which removed systematic differences of CO2 fluxes measured at two EC towers. This analysis was made for a data set where (i) only similar weather conditions at the two sites were included, and (ii) an unfiltered one. The extended approach, applied to weather-filtered data for separation distances of 95 and 173 m gave uncertainty estimates in best correspondence with an independent reference method. The introduced correction for systematic flux differences considerably reduced the overestimation of the two-tower based uncertainty of net CO2 flux measurements and decreased the sensitivity of results to tower distance. We therefore conclude that corrections for systematic flux differences (e.g., caused by different environmental conditions at both EC towers) can help to apply the two-tower approach to more site pairs with less ideal conditions.

The field of volume visualization has undergone rapid development during the past years, both due to advances in suitable computing hardware and due to the increasing availability of large volume datasets. Recent work has focused on increasing the visual realism in Direct Volume Rendering (DVR) by integrating a number of visually plausible but often effect-specific rendering techniques, for instance modeling of light occlusion and depth of field. Besides yielding more attractive renderings, especially the more realistic lighting has a positive effect on perceptual tasks. Although these new rendering techniques yield impressive results, they exhibit limitations in terms of their exibility and their performance. Monte Carlo ray tracing (MCRT), coupled with physically based light transport, is the de-facto standard for synthesizing highly realistic images in the graphics domain, although usually not from volumetric data. Due to the stochastic sampling of MCRT algorithms, numerous effects can be achieved in a relatively straight-forward fashion. For this reason, we have developed a practical framework that applies MCRT techniques also to direct volume rendering (DVR). With this work, we demonstrate that a host of realistic effects, including physically based lighting, can be simulated in a generic and flexible fashion, leading to interactive DVR with improved realism. In the hope that this improved approach to DVR will see more use in practice, we have made available our framework under a permissive open source license.

Background Cardiovascular magnetic resonance (CMR) strain imaging is an established technique to quantify myocardial deformation. However, to what extent left ventricular (LV) systolic strain, and therefore LV mechanics, reflects classical hemodynamic parameters under various inotropic states is still not completely clear. Therefore, the aim of this study was to investigate the correlation of LV global strain parameters measured via CMR feature tracking (CMR-FT, based on conventional cine balanced steady state free precession (bSSFP) images) with hemodynamic parameters such as cardiac index (CI), cardiac power output (CPO) and end-systolic elastance (Ees) under various inotropic states. Methods  Ten anaesthetized, healthy Landrace swine were acutely instrumented closed-chest and transported to the CMR facility for measurements. After baseline measurements, two steps were performed: (1) dobutamine-stress (Dobutamine) and (2) verapamil-induced cardiovascular depression (Verapamil). During each protocol, CMR images were acquired in the short axisand apical 2Ch, 3Ch and 4Ch views. MEDIS software was utilized to analyze global longitudinal (GLS), global circumferential (GCS), and global radial strain (GRS). Results Dobutamine significantly increased heart rate, CI, CPO and Ees, while Verapamil decreased them. Absolute values of GLS, GCS and GRS accordingly increased during Dobutamine infusion, while GLS and GCS decreased during Verapamil. Linear regression analysis showed a moderate correlation between GLS, GCS and LV hemodynamic parameters, while GRS correlated poorly. Indexing global strain parameters for indirect measures of afterload, such as mean aortic pressure or wall stress, significantly improved these correlations, with GLS indexed for wall stress reflecting LV contractility as the clinically widespread LV ejection fraction. Conclusion GLS and GCS correlate accordingly with LV hemodynamics under various inotropic states in swine. Indexing strain parameters for indirect measures of afterload substantially improves this correlation, with GLS being as good as LV ejection fraction in reflecting LV contractility. CMR-FT-strain imaging may be a quick and promising tool to characterize LV hemodynamics in patients with varying degrees of LV dysfunction.

Background Pancreatic panniculitis is characterized by subcutaneous fat necrosis and is a rare presentation of an underlying pancreatic disease, appearing in approximately 2–3% of all patients with a pancreatic disease. The nodules usually involve the lower extremities. Pancreatic panniculitis is commonly associated with acute or chronic pancreatitis, and occasionally with pancreatic cancer, especially acinar cell carcinoma. Case presentation A 77-year-old Caucasian woman with no significant medical history was referred to our center with multiple painful, itchy, and warm red/blue cutaneous nodules on the left lower leg. These skin lesions were consistent with the clinical diagnosis of panniculitis. The skin biopsy obtained showed a predominantly lobular panniculitis with fat necrosis of which the aspect was highly suspicious for pancreatic panniculitis. Further analysis revealed high lipase serum of > 3000 U/L (normal range < 60 U/L), and on computed tomography scan a mass located between the stomach and the left pancreas was seen. Endoscopic ultrasonography-guided fine-needle biopsy confirmed the diagnosis of acinar cell carcinoma. After discussing the patient in the pancreatobiliary multidisciplinary team meeting, laparoscopic distal pancreatectomy including splenectomy and en bloc wedge resection of the stomach due to tumor in-growth was performed. The cutaneous nodules on both legs disappeared 1–2 days after surgery. No long-term complications were reported during follow-up. One year after surgery, the patient presented with similar symptoms as preoperatively. Computed tomography scan showed local recurrence and distal metastases, which were subsequently confirmed by biopsy. She started with palliative folinic acid–fluorouracil–irinotecan–oxaliplatin chemotherapy but stopped after two cycles because of disease progression. The patient died 2 months later, 13 months after surgical resection. Conclusion This case illustrates the importance of clinically recognizing cutaneous nodules and pathological recognizing the specific microscopic changes as sign of a (malignant) pancreatic disease.

Background Ultrasound is an essential diagnostic examination used in several medical specialties. However, the quality of ultrasound examinations is dependent on mastery of certain skills, which may be difficult and costly to attain in the clinical setting. This study aimed to explore mastery learning for trainees practicing general abdominal ultrasound using a virtual reality simulator and to evaluate the associated cost per student achieving the mastery learning level. Methods Trainees were instructed to train on a virtual reality ultrasound simulator until the attainment of a mastery learning level was established in a previous study. Automated simulator scores were used to track performances during each round of training, and these scores were recorded to determine learning curves. Finally, the costs of the training were evaluated using a micro-costing procedure. Results Twenty-one out of the 24 trainees managed to attain the predefined mastery level two times consecutively. The trainees completed their training with a median of 2h38min (range: 1h20min-4h30min) using a median of 7 attempts (range: 3–11 attempts) at the simulator test. The cost of training one trainee to the mastery level was estimated to be USD 638. Conclusion Complete trainees can obtain mastery learning levels in general abdominal ultrasound examinations within 3 hours of training in the simulated setting and at an average cost of USD 638 per trainee. Future studies are needed to explore how the cost of simulation-based training is best balanced against the costs of clinical training.

Background Ultrasound is a safe and effective diagnostic tool used within several specialties. However, the quality of ultrasound scans relies on sufficiently skilled clinician operators. The aim of this study was to explore the validity of automated assessments of upper abdominal ultrasound skills using an ultrasound simulator. Methods Twenty five novices and five experts were recruited, all of whom completed an assessment program for the evaluation of upper abdominal ultrasound skills on a virtual reality simulator. The program included five modules that assessed different organ systems using automated simulator metrics. We used Messick’s framework to explore the validity evidence of these simulator metrics to determine the contents of a final simulator test. We used the contrasting groups method to establish a pass/fail level for the final simulator test. Results Thirty seven out of 60 metrics were able to discriminate between novices and experts ( p  < 0.05). The median simulator score of the final simulator test including the metrics with validity evidence was 26.68% (range: 8.1–40.5%) for novices and 85.1% (range: 56.8–91.9%) for experts. The internal structure was assessed by Cronbach alpha (0.93) and intraclass correlation coefficient (0.89). The pass/fail level was determined to be 50.9%. This pass/fail criterion found no passing novices or failing experts. Conclusions This study collected validity evidence for simulation-based assessment of upper abdominal ultrasound examinations, which is the first step toward competency-based training. Future studies may examine how competency-based training in the simulated setting translates into improvements in clinical performances.

•Most Dutch medical oncologists face dilemmas regarding nonreimbursed anticancer medicines.•Substantial differences exist in both clinical practices and moral perspectives regarding access.•These differences among medical oncologists lead to disparities in patient access.•Fewer than half inform patients about nonreimbursed medicines; most do not.•Dutch oncologists face OOP payment requests but rarely allow patients to pay. Timelines for market authorization and reimbursement for anticancer medicines differ across European countries. Therefore, medical oncologists may face periods when promising anticancer medicines are not reimbursed, prompting ethical concerns about equitable access, particularly in publicly funded healthcare systems, such as the Netherlands. This study explores Dutch medical oncologists’ experiences and moral perspectives regarding access to EU-authorized nonreimbursed anticancer medicines and assesses practice variation. A survey targeted 378 Dutch medical oncologists from all hospitals to explore their experiences, perspectives, and perceived responsibilities, as well as hospital policies regarding nonreimbursed EU-authorized anticancer medicines and their opinions on out-of-pocket payments and information provision. Responses were provided by 132 medical oncologists (response rate of 34.9%), with 104 (78.8%) reporting that they sought access to nonreimbursed medicines in the past three years for one or more patients, primarily through manufacturer-funded “free-of-charge” programs (n = 77/104; 74,0%), clinical trials referral (n = 46/104; 44.2%) or clinical trials at their own hospital (n = 45/104; 43.3%), insurance leniency (n = 45/104; 43.3%), or the Dutch Drug Access Protocol (n = 42/104; 40.4%). While 48.5% felt responsible for seeking access to nonreimbursed medicines, 40.9% did not. Respondents mentioned different hospital policies on drug access. In the past three years, 69.5% (n = 91/131) of respondents had received patient inquiries about out-of-pocket (OOP) payment, but only 3.1% (n = 4/131) had actually prescribed OOP financed medicines. Fewer than half of the respondents (44.7%; n = 59/132) informed patients about nonreimbursed treatment options. Oncologists expressed strong concerns about financial toxicity, inequities in access, and threats to solidarity-based health care. The majority of Dutch medical oncologists encounter EU-authorized, nonreimbursed anticancer medicines and report substantial variation in related practices and ethical views. In the absence of a national access framework, availability often depends on individual physicians, leading to potential inequities. National regulation is recommended to ensure consistent and equitable access for all patients.

Modeling net ecosystem exchange (NEE) at the regional scale with land surface models (LSMs) is relevant for the estimation of regional carbon balances, but studies on it are very limited. Furthermore, it is essential to better understand and quantify the uncertainty of LSMs in order to improve them. An important key variable in this respect is the prognostic leaf area index (LAI), which is very sensitive to forcing data and strongly affects the modeled NEE. We applied the Community Land Model (CLM4.5-BGC) to the Rur catchment in western Germany and compared estimated and default ecological key parameters for modeling carbon fluxes and LAI. The parameter estimates were previously estimated with the Markov chain Monte Carlo (MCMC) approach DREAM.sub.(zs) for four of the most widespread plant functional types in the catchment. It was found that the catchment-scale annual NEE was strongly positive with default parameter values but negative (and closer to observations) with the estimated values. Thus, the estimation of CLM parameters with local NEE observations can be highly relevant when determining regional carbon balances. To obtain a more comprehensive picture of model uncertainty, CLM ensembles were set up with perturbed meteorological input and uncertain initial states in addition to uncertain parameters. C.sub.3 grass and C.sub.3 crops were particularly sensitive to the perturbed meteorological input, which resulted in a strong increase in the standard deviation of the annual NEE sum (σ.sub. ∑ NEE) for the different ensemble members from ∼ 2 to 3 g C m.sup.-2 yr.sup.-1 (with uncertain parameters) to ∼ 45 g C m.sup.-2 yr.sup.-1 (C.sub.3 grass) and ∼ 75 g C m.sup.-2 yr.sup.-1 (C.sub.3 crops) with perturbed forcings. This increase in uncertainty is related to the impact of the meteorological forcings on leaf onset and senescence, and enhanced/reduced drought stress related to perturbation of precipitation. The NEE uncertainty for the forest plant functional type (PFT) was considerably lower (σ.sub. ∑ NEE ∼ 4.0-13.5 g C m.sup.-2 yr.sup.-1 with perturbed parameters, meteorological forcings and initial states). We conclude that LAI and NEE uncertainty with CLM is clearly underestimated if uncertain meteorological forcings and initial states are not taken into account.