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Supplementary Table 1. Hazard ratios of GI cancer overall by sex

Supplementary Table 2. Hazard ratios of GI cancer subsites by sex

Background and aims: High-density lipoproteins (HDL) of patients with type 2 diabetes mellitus (T2DM) have impaired anti-inflammatory activities. The anti-inflammatory activity of HDL has been determined ex vivo after isolation by different methods from blood mostly obtained after overnight fasting. We first determined the effect of the HDL isolation method, and subsequently the effect of food intake on the anti-inflammatory function of HDL from T2DM patients. Methods: Blood was collected from healthy controls and T2DM patients after an overnight fast, and from T2DM patients 3 h after breakfast (n = 17 each). HDL was isolated by a two-step density gradient ultracentrifugation in iodixanol (HDLDGUC2), by sequential salt density flotation (HDLSEQ) or by PEG precipitation (HDLPEG). The anti-inflammatory function of HDL was determined by the reduction of the TNFα-induced expression of VCAM-1 in human coronary artery endothelial cells (HCAEC) and retinal endothelial cells (REC). Results: HDL isolated by the three different methods from healthy controls inhibited TNFα-induced VCAM-1 expression in HCAEC. With apoA-I at 0.7 μM, HDLDGUC2 and HDLSEQ were similarly effective (16% versus 14% reduction; n = 3; p > 0.05) but less effective than HDLPEG (28%, p < 0.05). Since ultracentrifugation removes most of the unbound plasma proteins, we used HDLDGUC2 for further experiments. With apoA-I at 3.2 μM, HDL from fasting healthy controls and T2DM patients reduced TNFα-induced VCAM-1 expression in HCAEC by 58 ± 13% and 51 ± 20%, respectively (p = 0.35), and in REC by 42 ± 13% and 25 ± 18%, respectively (p < 0.05). Compared to preprandial HDL, postprandial HDL from T2DM patients reduced VCAM-1 expression by 56 ± 16% (paired test: p < 0.001) in HCAEC and by 34 ± 13% (paired test: p < 0.05) in REC. Conclusions: The ex vivo anti-inflammatory activity of HDL is affected by the HDL isolation method. Two-step ultracentrifugation in an iodixanol gradient is a suitable method for HDL isolation when testing HDL anti-inflammatory function. The anti-inflammatory activity of HDL from overnight fasted T2DM patients is significantly impaired in REC but not in HCAEC. The anti-inflammatory function of HDL is partly restored by food intake.

Introduction Mitotane is the only drug registered specifically for adrenocortical carcinoma. Finding the optimal dose for a patient is difficult due to large differences in bioavailability, toxicity and effect. We therefore look to improve personalized dosing of mitotane. Areas covered We searched PubMed for studies related to mitotane dosing, pharmacokinetics, pharmacogenetics and combination therapy. Comparison of different dosing strategies have not resulted in an optimal advice. Several computerized pharmacokinetic models have been proposed to predict plasma levels. The current pharmacokinetic models do not explain the full variance in plasma levels. Pharmacogenetics have been proposed to find the unexplained variance. Studies on combination therapy have not yet led to a potential dose adjustment for mitotane. Expert opinion Computerized pharmacokinetics models are promising tools to predict plasma levels, further validation is needed. Pharmacogenetics are introduced in these models, but more research is required before clinical application. We believe that in the near future, personalized mitotane dosage will be aided by a validated web-based pharmacokinetic model with good predictive ability based primarily on clinical characteristics, adjustable for actual plasma levels and dosage.

Background A variety of prediction models concerning COVID-19 have been proposed since onset of the pandemic, but to this date no gold standard exists. Mortality rates show a sharp increase with advancing age but with the large heterogeneity of this population in terms of comorbidities, vulnerability and disabilities, identifying risk factors is difficult. Therefore, we aimed to research the multidimensional concept of frailty, measured by the Acute Presenting Older Patient (APOP)-screener, as a risk factor for in-hospital mortality in older COVID-19 patients. Methods All consecutive patients of 70 years or older, with a PCR confirmed COVID-19 infection and a completed APOP-score, presenting at the Emergency Department (ED) of the Jeroen Bosch Hospital, the Netherlands, between February 27th 2020 and February 1st 2021 were retrospectively included. We gathered baseline characteristics and scored the CCI and CFS from patient records. The primary outcome was in-hospital mortality. Results A total of 292 patients met the inclusion criteria. Approximately half of the patients were considered frail by the APOP or CFS. 127 patients (43.5%) scored frail on the CFS, 158 (54.1%) scored high risk on the APOP-screener. 79 patients (27.1%) died during their hospital admission. The APOP-screener showed a significantly elevated risk of in-hospital mortality when patients scored both high risk of functional and evidence of cognitive impairment (OR 2.24, 95% 1.18–4.25). Significant elevation of in-hospital mortality was found for the high CCI-scores (≥ 5)(OR 1.78, 95% 1.02–3.11), but not for the highest CFS category (5–9, frail) (OR 1.35, 95% 0.75–2.47). The discriminatory performance of the APOP, CFS and CCI were comparable (AUC resp. 0.59 (0.52–0.66), 0.54 (0.46–0.62) and 0.58 (0.51–0.65)). Conclusion Although the elevated risk for in-hospital mortality found for the most frail patients as scored by the APOP, this instrument has poor discriminatory value. Additionally, the CFS did not show significance in predicting in-hospital mortality and had a poor discriminatory value as well. Therefore, treatment decisions based on frailty or comorbidities alone should be made with caution. Approaching the heterogeneity of the older population by adding frailty as assessed by the APOP-score to existing prediction models may enhance the predictive value of these models.

The aim of this scoping review is to identify patient reported outcome measures (PROMs) in acute care settings, assess their psychometric properties and provide recommendations for their use in daily practice. We performed a search in the PubMed database to identify publications concerning PROMs in an acute care setting. The COSMIN checklist was used to assess the psychometric properties of the reported PROMs. We found 1407 publications and included 14 articles, describing 15 measures. Most publications provided limited information on psychometric properties. Three generic PROMs were deemed of adequate quality for use in acute care. We recommend future development and evaluation of PROMs focussing on acute care to further evaluate and improve the quality of acute care.

Context Pretreatment with α-adrenergic receptor blockers is recommended to prevent hemodynamic instability during resection of a pheochromocytoma or sympathetic paraganglioma (PPGL). Objective To determine which type of α-adrenergic receptor blocker provides the best efficacy. Design Randomized controlled open-label trial (PRESCRIPT; ClinicalTrials.gov NCT01379898) Setting Multicenter study including 9 centers in The Netherlands. Patients 134 patients with nonmetastatic PPGL. Intervention Phenoxybenzamine or doxazosin starting 2 to 3 weeks before surgery using a blood pressure targeted titration schedule. Intraoperative hemodynamic management was standardized. Main Outcome Measures Primary efficacy endpoint was the cumulative intraoperative time outside the blood pressure target range (ie, SBP >160 mmHg or MAP Results Median cumulative time outside blood pressure targets was 11.1% (interquartile range [IQR]: 4.3–20.6] in the phenoxybenzamine group compared to 12.2% (5.3–20.2)] in the doxazosin group (P = .75, r = 0.03). The hemodynamic instability score was 38.0 (28.8–58.0) and 50.0 (35.3–63.8) in the phenoxybenzamine and doxazosin group, respectively (P = .02, r = 0.20). The 30-day cardiovascular complication rate was 8.8% and 6.9% in the phenoxybenzamine and doxazosin group, respectively (P = .68). There was no mortality after 30 days. Conclusions The duration of blood pressure outside the target range during resection of a PPGL was not different after preoperative treatment with either phenoxybenzamine or doxazosin. Phenoxybenzamine was more effective in preventing intraoperative hemodynamic instability, but it could not be established whether this was associated with a better clinical outcome.

BackgroundDifferentiated thyroid cancer (DTC) reports a poorer health‐related quality of life (HRQoL) than a norm population. Patients' illness perceptions are modifiable and known associates of HRQoL in other cancers. The aim was to examine the relationship between illness perceptions and HRQoL among DTC survivors.MethodsDTC survivors registered in the Netherlands Cancer Registry diagnosed between 1990 and 2008, received a survey on illness perceptions (Brief‐Illness Perception Questionnaire; B‐IPQ) and HRQoL (European Organisation for Research and Treatment of Cancer, Quality of Life Questionnaire‐Core 30; EORTC QLQ‐C30). Multiple regression analyses were conducted investigating the relation between illness perceptions and HRQoL, while controlling for sociodemographic and clinical characteristics.ResultsTwo hundred and eighty‐four DTC survivors were included. DTC survivors who believed their illness had many negative consequences; who perceived their illness as controllable by treatment; who had strong beliefs symptoms could be attributed to their illness; and who had strong beliefs their illness causes negative emotions, reported a poorer HRQoL.ConclusionsStronger negative illness perceptions are related to a poorer HRQoL among DTC survivors.

Adrenocortical carcinoma affects one in 5 million children each year. Since prognosis for children older than 4 years is limited, clinicians often choose aggressive treatment with etoposide, doxorubicin, cisplatin (EDP) and mitotane after resection. However, little is known about the impact of EDP-mitotane in children. We provide an overview of case-reports and case series listing side-effects and neurotoxicity of EDP-mitotane in children. Fourteen studies were identified describing a range of gastro-intestinal, endocrine, developmental and neuropsychological side-effects. Neurotoxicity included motor- and speech delay, decreased concentration and lower school performance. These side-effects appear to be reversible after mitotane discontinuation. We have added our own experience with a 10 year old girl with advanced adrenocortical carcinoma treated with EDP and 2 years of mitotane after irradical resection. She developed an impactful, but reversible, decrease in cognitive development measured by a standardized neuropsychological assessment before, during and after mitotane therapy. This decrease was mostly measurable in terms of decreased processing speed and concentration and a significant drop in school performance. Combined with fatigue and insecurity, this caused problems in short-term memory and the need to change her school type. In conclusion, EDP-mitotane is associated with several side-effects including neurotoxicity in pediatric cases, all reversible after mitotane discontinuation.

Background: Presurgical treatment with an α-adrenergic receptor blocker is recommended to antagonize the catecholamine-induced α-adrenergic receptor mediated vasoconstriction in patients with pheochromocytoma or sympathetic paraganglioma (PPGL). There is, however, a considerable interindividual variation in the dose-response relationship regarding the magnitude of blood pressure reduction or the occurrence of side effects. We hypothesized that genetically determined differences in α-adrenergic receptor activity contribute to this variability in dose-response relationship. Methods: Thirty-one single-nucleotide polymorphisms (SNPs) of the α1A, α1B, α1D adrenoreceptor (ADRA1A, ADRA1B, ADRA1D) and α2A, α2B adrenoreceptor (ADRA2A, ADRA2B) genes were genotyped in a group of 116 participants of the PRESCRIPT study. Haplotypes were constructed after determining linkage disequilibrium blocks. Results: The ADRA1B SNP rs10515807 and the ADRA2A SNPs rs553668/rs521674 were associated with higher dosages of α-adrenergic receptor blocker (p < 0.05) and with a higher occurrence of side effects (rs10515807) (p = 0.005). Similar associations were found for haplotype block 6, which is predominantly defined by rs10515807. Conclusions: This study suggests that genetic variability of α-adrenergic receptor genes might be associated with the clinically observed variation in beneficial and adverse therapeutic drug responses to α-adrenergic receptor blockers. Further studies in larger cohorts are needed to confirm our observations.

Simple Summary: Patients with the rare cancer adrenocortical carcinoma are exposed to many symptoms and treatment side-effects. Research on how this can affect their health-related quality of life (HRQoL) is limited, however. This article includes the first assessment of HRQoL in a population-based cohort of patients with adrenocortical carcinoma with the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire and the newly developed disease-specific additional questionnaire ACC-QOL. The ACC-QOL has good psychometric properties in terms of validity, reliability, and responsiveness. Patients diagnosed more than 5 years ago reported a relatively good HRQoL compared with the Dutch reference population, but experienced residual fatigue and emotional problems. Patients after additional surgery reported a slightly lower HRQoL due to physical limitations. Patients who had recently received mitotane or chemotherapy reported a worse HRQoL and problems in many domains. This knowledge and the new disease-specific questionnaire can aid future research, side-effect monitoring, treatment guidance, and shared decision making. We aimed to develop a disease-specific adrenocortical carcinoma (ACC) health-related quality of life (HRQoL) questionnaire (ACC-QOL) and assess HRQoL in a population-based cohort of patients with ACC. Development was in line with European Organization for Research and Treatment of Cancer (EORTC) guidelines, though not an EORTC product. In phase I and II, we identified 90 potential HRQoL issues using literature and focus groups, which were reduced to 39 by healthcare professionals. Pilot testing resulted in 28 questions, to be used alongside the EORTC QLQ-C30. In Phase III, 100 patients with ACC were asked to complete the questionnaires twice in the PROFILES registry (3-month interval, respondents: first 67, second 51). Confirmatory factor analysis demonstrated the structural validity of 26 questions with their scale structure (mitotane side-effects, hypercortisolism/hydrocortisone effects, emotional effects). Internal consistency and reliability were good (Cronbach's alpha 0.897, Interclass correlation coefficient 0.860). Responsiveness analysis showed good discriminative ability (AUC 0.788). Patients diagnosed more than 5 years ago reported a good HRQoL compared with the Dutch reference population, but experienced residual fatigue and emotional problems. Patients who underwent recent treatment reported a lower HRQoL and problems in several domains. In conclusion, we developed an ACC-specific HRQoL questionnaire with good psychometric properties.

Background: Cross-sectional imaging regularly results in incidental discovery of adrenal tumours, requiring exclusion of adrenocortical carcinoma (ACC). However, differentiation is hampered by poor specificity of imaging characteristics. We aimed to validate a urine steroid metabolomics approach, using steroid profiling as the diagnostic basis for ACC. Methods: We did a prospective multicentre study in adult participants (age ≥18 years) with newly diagnosed adrenal masses. We assessed the accuracy of diagnostic imaging strategies based on maximum tumour diameter (≥4 cm vs

Background Despite adequate presurgical management, blood pressure fluctuations are common during resection of pheochromocytoma or sympathetic paraganglioma (PPGL). To a large extent, the variability in blood pressure control during PPGL resection remains unexplained. Adrenomedullin and B-type natriuretic peptide, measured as MR-proADM and NT-proBNP, respectively, are circulating biomarkers of cardiovascular dysfunction. We investigated whether plasma levels of MR-proADM and NT-proBNP are associated with blood pressure fluctuations during PPGL resection. Methods Study subjects participated in PRESCRIPT, a randomized controlled trial in patients undergoing PPGL resection. MR-proADM and NT-proBNP were determined in a single plasma sample drawn before surgery. Multivariable linear and logistic regression analyses were used to explore associations between these biomarkers and blood pressure fluctuations, use of vasoconstrictive agents during surgery as well as the occurrence of perioperative cardiovascular events. Results A total of 126 PPGL patients were included. Median plasma concentrations of MR-proADM and NT-proBNP were 0.51 (0.41–0.63) nmol/L and 68.7 (27.9–150.4) ng/L, respectively. Neither MR-proADM nor NT-proBNP were associated with blood pressure fluctuations. There was a positive correlation between MR-proADM concentration and the cumulative dose of vasoconstrictive agents (03B2 0.44, P =0.001). Both MR-proADM and NT-proBNP were significantly associated with perioperative cardiovascular events (OR: 5.46, P =0.013 and OR: 1.54, P =0.017, respectively). Conclusions plasma MR-proADM or NT-proBNP should not be considered as biomarkers for the presurgical risk assessment of blood pressure fluctuations during PPGL resection. Future studies are needed to explore the potential influence of these biomarkers on the intraoperative requirement of vasoconstrictive agents and the perioperative cardiovascular risk.

This research study aimed to investigate the association between demographic and operational factors and emergency medical services (EMS) missions ending in non-conveyance (NC) due to patient-initiated refusal (PIR). We conducted a retrospective population-based registry study by analyzing 67,620 EMS missions dispatched to the scene during 2018 in the Riyadh province. First, the number and percentages of conveyances statuses were calculated. Then, using crude and adjusted linear and logistic regression analysis, we determined which characteristics were predictors of NC due to PIR. We found that 23,991 (34.4%) of missions ended in NC due to PIR, and 5969 ended in EMS-initiated refusal (8.6%). NC rates due to PIR were higher for women, adults, for missions in Riyadh city, during nighttime, for medical emergencies, and for advanced life support (ALS) crews. We also found the following additional predictors significantly associated with the odds of NC due to PIR in crude regression analyses: age category, geographical location, EMS-shift, time of call, emergency type, and response time. We conclude that the NC rate represents half of all missions for patients requesting EMS, and the rate in Riyadh city has increased compared to previous studies. Most NC cases occur for the highest urgency level of medical emergency type in Riyadh city during the nighttime with ALS crews. NC due to PIR involves younger patients more than elderly, and females more than males. This study’s findings have provided empirical evidence that indicate that conducting further studies involving EMS providers, patients, and the public to identify precise and detailed reasons is required.

Introduction Adrenocortical carcinoma (ACC) is a rare cancer that commonly spreads to the liver, lungs and lymph nodes. Bone metastases are infrequent. Objective The aim of this report was to describe the clinical characteristics, survival perspective, prognostic factors and frequency of adverse skeletal-related events (SREs) in patients with ACC who developed bone metastasis. Methods This is a retrospective, observational, multicenter, multinational study of patients diagnosed with bone metastases from ACC who were treated and followed up in three European countries (France, Italy and The Netherlands) and one center in the United States. Results Data of 156 patients were captured. The median overall survival was 11 months. SREs occurred in 47% of patients: 17% bone fractures, 17% spinal cord compression, 1% hypercalcemia, 12% developed more than one SRE. In multivariate analysis, cortisol hypersecretion was the only prognostic factor significantly associated with a higher mortality risk (hazard ratio (HR) 2.24, 95% confidence interval (CI): 1.19–4.23, P = 0.013) and with the development of a SREs (of border line significance). The administration of antiresorptive therapies (bisphosphonates and denosumab) was associated with a lower risk of death, even if not significant, and their survival benefit appeared confined in patients attaining serum mitotane levels within the therapeutic range. Conclusion Bone metastases in ACC patients are associated with poor prognosis and high risk of SREs. Cortisol hypersecretion was the only prognostic factor suggesting a potential benefit from antisecretory medications. The therapeutic role of bisphosphonates and denosumab to improve patient outcome deserves to be tested in a prospective clinical trial.

A relevant issue on the treatment of adrenocortical carcinoma (ACC) concerns the optimal duration of adjuvant mitotane treatment. We tried to address this question, assessing whether a correlation exists between the duration of adjuvant mitotane treatment and recurrence-free survival (RFS) of patients with ACC. We conducted a multicenter retrospective analysis on 154 ACC patients treated for ≥12 months with adjuvant mitotane after radical surgery and who were free of disease at the mitotane stop. During a median follow-up of 38 months, 19 patients (12.3%) experienced recurrence. We calculated the RFS after mitotane (RFSAM), from the landmark time-point of mitotane discontinuation, to overcome immortal time bias. We found a wide variability in the duration of adjuvant mitotane treatment among different centers and also among patients cared for at the same center, reflecting heterogeneous practice. We did not find any survival advantage in patients treated for longer than 24 months. Moreover, the relationship between treatment duration and the frequency of ACC recurrence was not linear after stratifying our patients in tertiles of length of adjuvant treatment. In conclusion, the present findings do not support the concept that extending adjuvant mitotane treatment over two years is beneficial for ACC patients with low to moderate risk of recurrence.

Background Mitotane is the only approved treatment for patients with adrenocortical carcinoma (ACC). A better explanation for the variability in the pharmacokinetics (PK) of mitotane, and the optimization and individualization of mitotane treatment, is desirable for patients. Objectives This study aims to develop a population PK (PopPK) model to characterize and predict the PK profiles of mitotane in patients with ACC, as well as to explore the effect of genetic variation on mitotane clearance. Ultimately, we aimed to facilitate mitotane dose optimization and individualization for patients with ACC. Methods Mitotane concentration and dosing data were collected retrospectively from the medical records of patients with ACC taking mitotane orally and participating in the Dutch Adrenal Network. PopPK modelling analysis was performed using NONMEM (version 7.4.1). Genotypes of drug enzymes and transporters, patient demographic information, and clinical characteristics were investigated as covariates. Subsequently, simulations were performed for optimizing treatment regimens. Results A two-compartment model with first-order absorption and elimination best described the PK data of mitotane collected from 48 patients. Lean body weight (LBW) and genotypes of CYP2C19*2 (rs4244285), SLCO1B3 699A>G (rs7311358) and SLCO1B1 571T>C (rs4149057) were found to significantly affect mitotane clearance (CL/F), which decreased the coefficient of variation (CV%) of the random inter-individual variability of CL/F from 67.0 to 43.0%. Fat amount (i.e. body weight − LBW) was found to significantly affect the central distribution volume. Simulation results indicated that determining the starting dose using the developed model is beneficial in terms of shortening the period to reach the therapeutic target and limit the risk of toxicity. A regimen that can effectively maintain mitotane concentration within 14–20 mg/L was established. Conclusions A two-compartment PopPK model well-characterized mitotane PK profiles in patients with ACC. The CYP2C19 enzyme and SLCO1B1 and SLCO1B3 transporters may play roles in mitotane disposition. The developed model is beneficial in terms of optimizing mitotane treatment schedules and individualizing the initial dose for patients with ACC. Further validation of these findings is still required. Electronic supplementary material The online version of this article (10.1007/s40262-020-00913-y) contains supplementary material, which is available to authorized users.

The purpose of this study was to explore differences in characteristics of missions dispatched by Emergency Medical Services (EMS) between rural and urban areas of Riyadh province in Saudi Arabia (SA). It also aimed at identifying weaknesses related to utilization and Response Time (RT). The study retrospectively evaluated 146,639 completed missions in 2018 by measuring the utilization rate in rural and urban areas. The study shows there are six times more ambulance crews available for rural areas compared to urban. There were 22.1 missions per 1000 urban inhabitants and 11.2 missions per 1000 in rural areas. The median RT for high urgent trauma cases was 20.2 min in rural compared to 15.2 min in urban areas (p &lt, 0.001). In urban areas, the median RT for high urgent medical cases was 16.1 min, while it was 15.2 min for high urgent trauma cases. Around 62.3% of emergency cases in urban and 56.5% in rural areas were responded to within 20.00 min. Women utilized EMS less frequently. The RT was increased in urban areas compared to previous studies. The RT in the central region of SA has been identified as equal, or less than 20.00 min in 62.4% of all emergency cases. To further improve adherence to the 20&prime, target, reorganizing the lowest urgent cases in the rural areas seems necessary.

Little is known about the impact of adrenocortical carcinoma (ACC) on health-related quality of life (HRQoL), and no disease-specific questionnaire exists. This qualitative study aimed to identify relevant domains of HRQoL for patients with ACC. In 2 focus group interviews, we discussed concerns regarding living with ACC and its treatments. The first group consisted of 6 patients on mitotane therapy and their partners or relatives, the second group of 4 patients after surgery alone and their partners. Inductive qualitative content analysis was used to analyze the interviews. We identified 4 domains related to HRQoL in patients with ACC, namely physical complaints, mental consequences, social consequences, and functional limitations. For example, physical complaints included symptoms of the disease and side effects of mitotane therapy; mental consequences included feeling insecure and living from scan to scan; and functional limitations included daily activities and mobility. We further found that patients’ experiences with the health care system and health care professionals and partner perspectives influence HRQoL. In conclusion, ACC has a large impact on HRQoL in 4 domains. These results can be used to improve communication about HRQoL issues. We will use our findings to generate a disease-specific questionnaire to measure HRQoL in patients with ACC.

BACKGROUND: Nonspecific complaints (NSC) at the Emergency Department (ED) are not well researched yet.OBJECTIVE: To investigate the number of patients who could be classified as having NSC early after arrival in the ED using an algorithm.METHOD: Retrospective cohort study was conducted among all hemodynamically stable non-trauma adult patients with MTS category orange/yellow visiting the ED. Patients who had no specific complaints/signs, predefined on a list, were categorized as NSC.RESULTS: In total, 2419 patients, of whom 102 (4.2%) presented with NSC. Hospitalization was more prevalent (85.3% vs. 69.0%, pCONCLUSION: Using an algorithm it is possible to identify NSC patients who have (worse) outcomes than those classified as SC.

ObjectivesTo identify the intergender variation of on-scene time (OST) for highly urgent emergency cases conveyed by emergency medical services (EMS) in Saudi Arabia and to assess other predictors of OST and hypothesise for possible factors delaying OST.DesignA retrospective population-based registry study.SettingRiyadh Province is the largest province in terms of population and the second in terms of geographical area.ParticipantsAll highly urgent transported patients from the scene to emergency departments, be they medical emergencies or trauma emergencies during 2018.Outcome measureOST difference between men and women transported by EMS.ResultsIn total, 21 878 patients were included for analysis: 33.9% women and 66.1% men. The median OST for women was 22 min (IQR 15–30) and 18 min (IQR 11–26) for men (pConclusionsThe median OST was longer than 15 min for more than half of transported cases. For medical cases, women had a longer median OST than men. Additional predictors associated with prolonged OST were the patient’s age, area (ie, urban vs rural), type of ambulance vehicle and season. These findings are hypothesis generating and require further studies.

Summary: Background & aims: Knowledge of postprandial glycemic response (PPGR) dynamics is important in nutrition management and diabetes research, care and (self)management. In daily life, food intake is the most important factor influencing the occurrence of hyperglycemia. However, the large variability in PPGR dynamics to different types of food is inadequately predicted by existing glycemic measures. The objective of this study was therefore to quantitatively describe PPGR dynamics using a systems approach. Methods: Postprandial glucose and insulin data were collected from literature for many different food products and mixed meals. The predictive value of existing measures, such as the Glycemic Index, was evaluated. A physiology-based dynamic model was used to reconstruct the full postprandial response profiles of both glucose and insulin simultaneously. Results: We collected a large range of postprandial glucose and insulin dynamics for 53 common food products and mixed meals. Currently available glycemic measures were found to be inadequate to describe the heterogeneity in postprandial dynamics. By estimating model parameters from glucose and insulin data, the physiology-based dynamic model accurately describes the measured data whilst adhering to physiological constraints. Conclusions: The physiology-based dynamic model provides a systematic framework to analyze postprandial glucose and insulin profiles. By changing parameter values the model can be adjusted to simulate impaired glucose tolerance and insulin resistance. Keywords: Postprandial glycemic response, Physiology-based dynamic model, Food intake, Computational modeling, Glucose, Insulin

Background: Studies investigating different medical conditions and settings have demonstrated mixed results regarding the weekend effect. However, data on the outcome of elderly patients hospitalised on weekends is scarce. The objective was to compare in-hospital and two-day mortality rates between elderly emergency department (ED) patients (>= 65 years) admitted on weekends versus weekdays. Methods: A retrospective cohort study of emergency department visits of internal medicine patients >= 65 years presenting to the emergency department between 01 and 09-2010 and 31-08-2012 was conducted. The weekend was defined as the period from midnight on Friday to midnight on Sunday. Results: Data on 3697 emergency department visits by elderly internal medicine patients (mean age 78.6 years old) were included. In total, 2743 emergency department visits (74.2%) resulted in hospitalisation, of which 22.9% occurred on weekends. Comorbidity and urgency levels were higher in patients admitted on weekends. In-hospital mortality was 11.4% for patients admitted on weekends compared with 8.9% on weekdays (OR 1.3, 95% CI 0.99-1.8). Two-day mortality was 3.2% in patients hospitalised on weekends versus 1.9% on weekdays (OR 1.7, 95% CI 0.99-2.9). Multivariable adjustment for age, comorbidity and triage level demonstrated comparable in-hospital and two-day mortality for weekend and week admission (ORadj 1.2, 95% CI 0.9-1.7 and ORadj 1.5, 95% CI 0.8-2.6, resp.). Conclusion: A small weekend effect was observed in elderly internal medicine patients, which was not statistically significant. This effect was partly explained by a higher comorbidity and urgency level in elderly patients hospitalised on weekends than during weekdays. Emergency care for the elderly is not compromised by adjusted logistics during the weekend.

Aim. - This study explores the changes in glucose-lowering drug (GLD) use before and after cancer diagnosis among patients with diabetes. Methods. - New GLD users (1998-2011) living in the Dutch ECR-PHARMO catchment area were selected from the PHARMO Database Network (n = 52,228). Those with a primary cancer diagnosis were considered cases (n = 3281) and matched with eligible controls (n = 12,891) without cancer during follow-up. Conditional logistic regression analysis was used to assess changes in GLD use, such as treatment add-ons, treatments drops and initiation of insulin, for cases compared with controls associated with specific cancer types in four time windows (6-3 and 0-3 months before cancer diagnosis; 0-3 and 3-6 months after cancer diagnosis). Results. - In the 3 months before cancer diagnosis, patients with upper gastrointestinal (GI) cancers (oesophageal, stomach, pancreatic, liver cancers) had higher odds of initiating insulin (OR: 9.3; 95% CI: 3.6-24.1); to a lesser extent, this was also observed in the 3 months prior to that (at 6 months, OR: 3.9; 95% CI: 1.31-2.1). Diagnosis of colorectal (OR: 3.4; 95% CI: 1.4-8.4), pulmonary (OR: 2.5; 95% CI: 1.1-5.4) and upper GI (OR: 13.6; 95% CI: 5.0-36.9) cancers was associated with increased odds of initiating insulin in the 3 months after cancer diagnosis. During all study time windows, the odds of treatment drops were higher for patients with upper GI cancers whereas, for most other cancers, these odds were higher only after a diagnosis of cancer. Conclusion. - The greater odds of initiating insulin during the 6 months prior to diagnosis of upper GI cancers suggest reverse causation. After cancer diagnosis, drops in use of GLDs was commonly seen. (C) 2017 Elsevier Masson SAS. All rights reserved.

Background: The ESE-ENSAT guidelines on the management of adrenocortical carcinoma (ACC) suggest adjuvant mitotane for patients at high risk of recurrence following radical surgery. This indication has a limited evidence base, lacking results from randomized controlled trials. No suggestion for or against adjuvant mitotane in low-risk patients was given, since studies did not stratify patients for prognosis. The randomized controlled study ADIUVO compared the efficacy of adjuvant mitotane treatment vs. observation in prolonging recurrence-free survival (RFS) in ACC patients at low-intermediate risk of recurrence. Methods: The main inclusion criteria were: stage I-III ACC, R0 surgery, and Ki-67 ≤10%. Patients were randomly assigned 1:1 to adjuvant mitotane (MIT) or observation (OBS). The primary endpoint of the study was RFS. Patients who refused randomization were offered inclusion in the ADIUVO OBSERVATIONAL study. In this prospective, observational study, patients were managed as in the ADIUVO study. A total of 91 patients were enrolled in ADIUVO, 45 in the MIT and 46 in the OBS arm. Baseline characteristics of patients were perfectly matched between the 2 arms: median age, 51 vs. 50.5 years; female, 73% vs. 67%; stage I, 20% vs. 26%; stage II, 67% vs. 63%, stage III, 13% vs. 11%; ACC secretion 44% vs. 36%; Weiss 5 vs. 5; respectively. In ADIUVO OBSERVATIONAL, 42 patients were treated with mitotane and 53 were untreated. Baseline characteristics of patients were matched between the 2 groups and with MIT and OBS groups in ADIUVO. Thus, the ADIUVO OBSERVATIONAL cohorts could be analyzed in parallel to those of ADIUVO. Results: In the ADIUVO study, recurrences were 8 in the MIT and 11 in the OBS arm, while deaths were 2 and 5, respectively. RFS and overall survival (OS) did not significantly differ between the 2 arms. Tumor size was a predictor of RFS in multivariable analysis. In the OBS arm, the HR for recurrence was 1.321 (95%CI, 0.55–3.32, p=0.54) and HR for death 2.171 (95%CI, 0.52–12.12, p=0.29). The survival analysis in the ADIUVO OBSERVATIONAL study confirmed the findings of ADIUVO. Given the outcome of both studies, the NNT is 55. Conclusions: ACC patients at low-intermediate risk of recurrence after surgery are a minority; however, they show a far better prognosis than expected (5-year RFS is about 75%) and do not benefit significantly from adjuvant mitotane. The results of the ADIUVO study do not support routine use of adjuvant mitotane in this subset of patients, who may thus avoid a potentially toxic treatment. This is an important step toward personalization of ACC care.

Background: Adrenocortical carcinoma (ACC) has an aggressive but heterogeneous behaviour. ENSAT stage and Ki67 proliferation index are used to predict clinical outcome but are limited in distinguishing patients with different risk of disease progress. We aimed to validate the prognostic role of a previously proposed points-based score (mGRAS) in a large ACC cohort. Methods: We included ACC patients who underwent adrenalectomy between 2010 and 2019, had complete clinical and histopathological data, and did not participate in our previous studies (Libe et al. Ann Oncol 2015; Lippert et al. JCEM 2018). The mGRAS score was calculated as follows: age ( Results: A total of 942 ACC patients from 14 ENSAT centres were included (38% men; median age 50yrs (interquartile range 38, 61)). The four mGRAS groups showed superior prognostic discrimination compared to the individual clinical and histological parameters for both PFS and DSS (C-index 0.71, R2D=0.30 and 0.77, R2D=0.46, respectively); ENSAT staging was the second best discriminator (C-index 0.67, R2D 0.21 and 0.72, R2D=0.35, respectively). An even better prognostic discrimination was observed using the ten mGRAS scores individually (C-index 0.73, R2D=0.30, and 0.79, R2D=0.45 for PFS and DSS, respectively). The superiority of mGRAS was confirmed when separately considering patients treated or untreated with adjuvant mitotane (n=481 vs 314). In mitotane-treated patients, the four mGRAS groups showed better performance in predicting PFS than Ki67 index (C-index 0.66, R2D 0.18 vs C-index 0.62, R2D 0.12). Conclusion: The prognostic performance of mGRAS is superior to that of ENSAT staging and Ki67. This simple score may guide personalised treatment decisions in patients with ACC, e.g. regarding the need for adjuvant therapy and frequency of monitoring.

The Eindhoven Diabetes Education Simulator project was initiated to develop an educational solution that helps diabetes patients understand and learn more about their diabetes. This article describes the identification of user preferences for the development of such solutions. Young seniors (aged 50–65 years) with type 2 diabetes were chosen as the target group because they are likely to have more affinity with digital devices than older people and because 88% of the Dutch diabetes population is >50 years of age. Data about the target group were gathered through literature research and interviews. The literature research covered data about their device use and education preferences. To gain insight into the daily life of diabetes patients and current diabetes education processes, 20 diabetes patients and 10 medical experts were interviewed. The interviews were analyzed using affinity diagrams. Those diagrams, together with the literature data, formed the basis for two personas and corresponding customer journey maps. Literature showed that diabetes prevalence is inversely correlated to educational level. Computer and device use is relatively low within the target group, but is growing. The interviews showed that young seniors like to play board, card, and computer games, with others or alone. Family and loved ones play an important role in their lives. Medical experts are crucial in the diabetes education of young senior diabetes patients. These findings are translated into a list of design aspects that can be used for creating educational solutions.

Muscle weakness and exercise intolerance negatively affect the quality of life of patients with mitochondrial myopathy. Short-term dietary nitrate supplementation has been shown to improve exercise performance and reduce oxygen cost of exercise in healthy humans and trained athletes. We investigated whether 1 wk of dietary inorganic nitrate supplementation decreases the oxygen cost of exercise and improves mitochondrial function in patients with mitochondrial myopathy. Ten patients with mitochondrial myopathy (40 ± 5 yr, maximal whole body oxygen uptake = 21.2 ± 3.2 ml·min−1·kg body wt−1, maximal work load = 122 ± 26 W) received 8.5 mg·kg body wt−1·day−1inorganic nitrate (~7 mmol) for 8 days. Whole body oxygen consumption at 50% of the maximal work load, in vivo skeletal muscle oxidative capacity (evaluated from postexercise phosphocreatine recovery using31P-magnetic resonance spectroscopy), and ex vivo mitochondrial oxidative capacity in permeabilized skinned muscle fibers (measured with high-resolution respirometry) were determined before and after nitrate supplementation. Despite a sixfold increase in plasma nitrate levels, nitrate supplementation did not affect whole body oxygen cost during submaximal exercise. Additionally, no beneficial effects of nitrate were found on in vivo or ex vivo muscle mitochondrial oxidative capacity. This is the first time that the therapeutic potential of dietary nitrate for patients with mitochondrial myopathy was evaluated. We conclude that 1 wk of dietary nitrate supplementation does not reduce oxygen cost of exercise or improve mitochondrial function in the group of patients tested.

Background Capillary refill time (CRT) is a clinical test used to evaluate the circulatory status of patients; various methods are available to assess CRT. Conventional clinical research often demands large numbers of patients, making it costly, labor-intensive, and time-consuming. We studied the interobserver agreement on CRT in a nationwide study by using a novel method of research called flash mob research (FMR). Methods Physicians in the Netherlands were recruited by using word-of-mouth referrals, conventional media, and social media to participate in a nationwide, single-day, "nine-to-five," multicenter, cross-sectional, observational study to evaluate CRT. Patients aged ≥ 18 years presenting to the ED or who were hospitalized were eligible for inclusion. CRT was measured independently (by two investigators) at the patient's sternum and distal phalanx after application of pressure for 5 s (5s) and 15 s (15s). Results On October 29, 2014, a total of 458 investigators in 38 Dutch hospitals enrolled 1,734 patients. The mean CRT measured at the distal phalanx were 2.3 s (5s, SD 1.1) and 2.4 s (15s, SD 1.3). The mean CRT measured at the sternum was 2.6 s (5s, SD 1.1) and 2.7 s (15s, SD 1.1). Interobserver agreement was higher for the distal phalanx (κ value, 0.40) than for the sternum (κ value, 0.30). Conclusions Interobserver agreement on CRT is, at best, moderate. CRT measured at the distal phalanx yielded higher interobserver agreement compared with sternal CRT measurements. FMR proved a valuable instrument to investigate a relatively simple clinical question in an inexpensive, quick, and reliable manner.

Adrenocortical carcinoma (ACC) is diagnosed using the histopathological Weiss score (WS), but remains clinically elusive unless it has metastasized or grows locally invasive. Previously, we proposed the objective IGF2 methylation score as diagnostic tool for ACC. This multicenter European cohort study validates these findings. Patient and tumor characteristics were obtained from adrenocortical tumor patients. DNA was isolated from frozen specimens, where after DMR2, CTCF3, and H19 were pyrosequenced. The predictive value of the methylation score for malignancy, defined by the WS or metastasis development, was assessed using receiver operating characteristic curves and logistic and Cox regression analyses. Seventy-six ACC patients and 118 patients with adrenocortical adenomas were included from seven centers. The methylation score and tumor size were independently associated with the pathological ACC diagnosis (OR 3.756 95% CI 2.224–6.343; OR 1.467 95% CI 1.202–1.792, respectively; Hosmer–Lemeshow test P = 0.903), with an area under the curve (AUC) of 0.957 (95% CI 0.930–0.984). The methylation score alone resulted in an AUC of 0.910 (95% CI 0.866–0.952). Cox regression analysis revealed that the methylation score, WS and tumor size predicted development of metastases in univariate analysis. In multivariate analysis, only the WS predicted development of metastasis (OR 1.682 95% CI 1.285–2.202; P < 0.001). In conclusion, we validated the high diagnostic accuracy of the IGF2 methylation score for diagnosing ACC in a multicenter European cohort study. Considering the known limitations of the WS, the objective IGF2 methylation score could potentially provide extra guidance on decisions on postoperative strategies in adrenocortical tumor patients.

Insight into the health-related quality of life (HRQoL) impact of adrenocortical carcinoma (ACC) is important. The disease and its treatment options potentially have an impact on HRQoL. For patients with limited survival, HRQoL research is of utmost importance. We will therefore provide an overview of HRQoL studies in patients with ACC. We found six studies that measured HRQoL in 323 patients with ACC (3 cross-sectional, 1 cohort, 2 trials), all indicating a reduced HRQoL compared to the general population. The FIRMACT trial found that HRQoL of patients with ACC was reduced compared to the general population, and that chemotherapy-mitotane further reduced HRQoL even though survival improved. Clinical aspects of the disease, including cortisol and aldosterone production and adrenal insufficiency have shown great impact on HRQoL in benign disease, even after the recovery of hormonal status. However, the impact of malignant adrenal disease and treatment options on HRQoL including adrenalectomy, radiotherapy, mitotane therapy, and chemotherapy have not been sufficiently studied in patients with ACC. Although the number of HRQoL studies in patients with ACC is limited, the existing literature does indicate that ACC has a large impact on patients’ HRQoL, with disease specific aspects. Further HRQoL research in patients with ACC is essential to improve patient-centered care, preferably by using an ACC-specific HRQoL questionnaire.

Background: Adrenocortical carcinoma (ACC) is a rare tumor entity with restricted therapeutic opportunities. HSP90 (Heat Shock Protein 90) chaperone activity is fundamental for cell survival and contributes to different oncogenic signaling pathways. Indeed, agents targeting HSP90 function have shown therapeutic efficacy in several cancer types. We have examined the expression of HSP90 in different adrenal tumors and evaluated the use of HSP90 inhibitors in vitro as possible therapy for ACC.Methods: Immunohistochemical expression of HSP90 isoforms was investigated in different adrenocortical tumors and associated with clinical features. Additionally, a panel of N-terminal (17-allylamino-17-demethoxygeldanamycin (17-AAG), luminespib, and ganetespib) and C-terminal (novobiocin and silibinin) HSP90 inhibitors were tested on various ACC cell lines.Results: Within adrenocortical tumors, ACC samples exhibited the highest expression of HSP90β. Within a cohort of ACC patients, HSP90β expression levels were inversely correlated with recurrence-free and overall survival. In functional assays, among five different compounds tested luminespib and ganetespib induced a significant decrease in cell viability in single as well as in combined treatments with compounds of the clinically used EDP-M scheme (etoposide, doxorubicin, cisplatin, mitotane). Inhibition of cell viability correlated furthermore with a decrease in proliferation, in cell migration and an increase in apoptosis. Moreover, analysis of cancer pathways indicated a modulation of the ERK1/2—and AKT—pathways by luminespib and ganetespib treatment.Conclusions: Our findings emphasize HSP90 as a marker with prognostic impact and promising target with N-terminal HSP90 inhibitors as drugs with potential therapeutic efficacy toward ACC.

Background The demand on Emergency Departments and acute medical services is increasing internationally, creating pressure on health systems and negatively influencing the quality of delivered care. Visible consequences of the increased demand on acute services is crowding and queuing. This manifests as delays in the Emergency Departments, adverse clinical outcomes and poor patient experience. Overview Despite the similarities in the UK’s and Dutch health care systems, such as universal health coverage, there are differences in the number of patients presenting at the Emergency Departments and the burden of crowding between these countries. Given the similarities in funding, this paper explores the similarities and differences in the organisational structure of acute care in the UK and the Netherlands. In the Netherlands, less patients are seen at the ED than in England and the admission rate is higher. GPs and so-called GP-posts serve 24/7 as gatekeepers in acute care, but EDs are heterogeneously organised. In the UK, the acute care system has a number of different access points and the accessibility of GPs seems to be suboptimal. Acute ambulatory care may relieve the pressure from EDs and Acute Medical Units. In both countries the ageing population leads to a changing case mix at the ED with an increased amount of multimorbid patients with polypharmacy, requiring generalistic and multidisciplinary care. Conclusion The acute and emergency care in the Netherlands and the UK face similar challenges. We believe that each system has strengths that the other can learn from. The Netherlands may benefit from an acute ambulatory care system and the UK by optimizing the accessibility of GPs 24/7 and improving signposting for urgent care services. In both countries the changing case mix at the ED needs doctors who are superspecialists instead of subspecialists. Finally, to improve the organisation of health care, doctors need to be visible medical leaders and participate in the organisation of care.

Aim: Use of tele-health programs and wearable sensors that allow patients to monitor their own vital signs have been expanded in response to COVID-19. We aimed to explore the utility of patient-held data during presentation as medical emergencies.Methods: We undertook a systematic scoping review of two groups of studies: studies using non-invasive vital sign monitoring in patients with chronic diseases aimed at preventing unscheduled reviews in primary care, hospitalization or emergency department visits and studies using vital sign measurements from wearable sensors for decision making by clinicians on presentation of these patients as emergencies. Only studies that described a comparator or control group were included. Studies limited to inpatient use of devices were excluded.Results: The initial search resulted in 896 references for screening, nine more studies were identified through searches of references. 26 studies fulfilled inclusion and exclusion criteria and were further analyzed. The majority of studies were from telehealth programs of patients with congestive heart failure or Chronic Obstructive Pulmonary Disease. There was limited evidence that patient held data is currently used to risk-stratify the admission or discharge process for medical emergencies. Studies that showed impact on mortality or hospital admission rates measured vital signs at least daily. We identified no interventional study using commercially available sensors in watches or smart phones.Conclusions: Further research is needed to determine utility of patient held monitoring devices to guide management of acute medical emergencies at the patients' home, on presentation to hospital and after discharge back to the community.

Background: Adrenocortical carcinoma (ACC) is a rare disease with often poor prognosis. Previous research has shown that surgery in a Dutch Adrenal Network (DAN) center increases the chance of survival. We aim to explore the determinants and survival of patients with ACC recently treated in the Netherlands both within and outside DAN centers. Methods: We analyzed retrospectively collected data from 172 adult patients with newly diagnosed ACC and 97 patients with recurrence or new metastases, registered between 2014 and 2019 in the Netherlands Cancer Registry. Differences in survival were analyzed with cox-regression analysis. Results: More than half of the new cases presented with advance disease (25.7% stage III, 34.6% stage IV) and the median survival was 29 months. The majority of treatments occurred within a DAN center (87.2% of surgery, compared to 56.4% between 1999 and 2009; and 94.5% of medical treatment). There were no differences in patient characteristics between the centers apart from a relatively high number of patients with stage IV disease outside DAN centers (47.2% vs. 28.7%). Adrenal resection and mitotane therapy both resulted in a significant survival benefit (resection HR 0.29, CI95%[0.17–0.49]; mitotane HR 0.61, CI95%[0.37–0.99], corrected for stage). Still, a remarkable proportion of patients with advanced disease received no mitotane treatment (39.8%). Due to the small number of patients treated outside DAN centers, survival benefits could not be tested. Conclusions: Centralization of ACC care in the Netherlands has improved since the previous report, but a further improvement in centralization of surgery can be made. Adrenal resection and mitotane treatment remain the main form of treatment, with a clear survival benefit. Further research is necessary to determine why mitotane treatment is withheld in a large proportion of patients with advance disease.

OBJECTIVE: This study was designed to define the concept of an educational diabetes game following a user-centered design approach.MATERIALS AND METHODS: The concept development of the Eindhoven Diabetes Education Simulator (E-DES) project can be divided in two phases: concept generation and concept evaluation. Four concepts were designed by the multidisciplinary development team based on the outcomes of user interviews. Four other concepts resulted from the Diabetes Game Jam. Several users and experts evaluated the concepts. These user evaluations and a feasibility analysis served as input for an overall evaluation and discussion by the development team resulting in the final concept choice.RESULTS: The four concepts of the development team are a digital board game, a quiz platform, a lifestyle simulator, and a puzzle game. The Diabetes Game Jam resulted in another digital board game, two mobile swipe games, and a fairy tale-themed adventure game. The combined user evaluations and feasibility analysis ranked the quiz platform and the digital board game equally high. Each of these games fits one specific subgroup of users best: the quiz platform best fits an eager-to-learn, more individualistic patient, whereas the board game best fits a less-eager-to-learn, family-oriented patient. The choice for a specific concept is therefore highly dependent on the choice of our specific target audience.CONCLUSIONS: The user-centered design approach with multiple evaluations has enabled us to choose the most promising concept from eight different options. A digital board game is chosen for further development because the target audience for E-DES is the less-motivated, family-oriented patients.