Dosimetric impact of bone marrow sparing for robustly optimized IMPT for locally advanced cervical cancer.

BACKGROUND AND PURPOSE: To investigate the trade-off between bone marrow sparing (BMS) and dose to organs at risk (OARs) for intensity modulated proton therapy (IMPT) for women with locally advanced cervical cancer (LACC). MATERIALS AND METHODS: Twenty LACC patients were retrospectively included. IMPT plans were created for each patient using automated treatment planning. These plans progressively reduced bone marrow mean doses by steps of 1 GyRBE, while constraining target coverage and conformality. The relation between bone marrow dose and bladder, small bowel, rectum, and sigmoid doses was evaluated. RESULTS: A total of 140 IMPT plans were created. Plans without BMS had an average [range] bone marrow mean dose of 17.3 [14.7-21.6] GyRBE , which reduced to 12.0 [10.0-14.0] GyRBE with maximum BMS. The mean OAR dose [range] increased modestly for 1 GyRBE BMS: 0.2 [0.0 - 0.6] GyRBE for bladder, 0.3 [-0.2 - 0.7] GyRBE for rectum, 0.4 [0.1 - 0.8] GyRBE for small bowel, and 0.2 [-0.2 - 0.4] GyRBE for sigmoid. Moreover, for maximum BMS, mean OAR doses [range] escalated by 3.3 [0.1 - 6.7] GyRBE for bladder, 5.8 [1.8 - 12.4] GyRBE for rectum, 3.9 [1.6 - 5.9] GyRBE for small bowel, and 2.7 [0.6 - 5.9] GyRBE for sigmoid. CONCLUSION: Achieving 1 GyRBE BMS for IMPT is feasible for LACC patients with limited dosimetric impact on other OARs. While further bone marrow dose reduction is possible for some patients, it may increase OAR doses substantially for others. Hence, we recommend a personalized approach when introducing BMS into clinical IMPT treatment planning to carefully assess individual patient benefits and risks.

Dragon 1 Protocol Manuscript: Training, Accreditation, Implementation and Safety Evaluation of Portal and Hepatic Vein Embolization (PVE/HVE) to Accelerate Future Liver Remnant (FLR) Hypertrophy.

STUDY PURPOSE: The DRAGON 1 trial aims to assess training, implementation, safety and feasibility of combined portal- and hepatic-vein embolization (PVE/HVE) to accelerate future liver remnant (FLR) hypertrophy in patients with borderline resectable colorectal cancer liver metastases. METHODS: The DRAGON 1 trial is a worldwide multicenter prospective single arm trial. The primary endpoint is a composite of the safety of PVE/HVE, 90-day mortality, and one year accrual monitoring of each participating center. Secondary endpoints include: feasibility of resection, the used PVE and HVE techniques, FLR-hypertrophy, liver function (subset of centers), overall survival, and disease-free survival. All complications after the PVE/HVE procedure are documented. Liver volumes will be measured at week 1 and if applicable at week 3 and 6 after PVE/HVE and follow-up visits will be held at 1, 3, 6, and 12 months after the resection. RESULTS: Not applicable. CONCLUSION: DRAGON 1 is a prospective trial to assess the safety and feasibility of PVE/HVE. Participating study centers will be trained, and procedures standardized using Work Instructions (WI) to prepare for the DRAGON 2 randomized controlled trial. Outcomes should reveal the accrual potential of centers, safety profile of combined PVE/HVE and the effect of FLR-hypertrophy induction by PVE/HVE in patients with CRLM and a small FLR. TRIAL REGISTRATION: Clinicaltrials.gov: NCT04272931 (February 17, 2020). Toestingonline.nl: NL71535.068.19 (September 20, 2019).

[18F]FDG and [18F]NaF as PET markers of systemic atherosclerosis progression: A longitudinal descriptive imaging study in patients with type 2 diabetes mellitus.

BACKGROUND: While [18F]-fluordeoxyglucose ([18F]FDG) uptake is associated with arterial inflammation, [18F]-sodium fluoride ([18F]NaF) is a marker for arterial micro-calcification. We aimed to investigate the prospective correlation between both PET markers over time and whether they are prospectively ([18F]FDG) and retrospectively ([18F]NaF) related to progression of systemic arterial disease in a longitudinal study in patients with type 2 diabetes mellitus (T2DM). METHODS: Baseline [18F]FDG PET/Low Dose (LD) Computed Tomography (CT) scans of ten patients with early T2DM without cardiovascular history (70% men, median age 63 years) were compared with five-year follow-up [18F]NaF/LDCT scans. Systemic activity was expressed as mean target-to-background ratio (meanTBR) by dividing the maximal standardized uptake value (SUVmax) of ten arteries by SUVmean of the caval vein. CT-assessed macro-calcifications were scored visually and expressed as calcified plaque (CP) score. Arterial stiffness was assessed with carotid-femoral pulse wave velocity (PWV). Five-year changes were expressed absolutely with delta (Δ) and relatively with %change. RESULTS: Baseline meanTBR[18F]FDG was strongly correlated with five-year follow-up meanTBR[18F]NaF (r = 0.709, P = .022). meanTBR[18F]NaF correlated positively with ΔCPscore, CPscore at baseline, and follow-up (r = 0.845, P = .002 and r = 0.855, P = .002, respectively), but not with %change in CPscore and PWV. CONCLUSION: This proof-of-concept study demonstrated that systemic arterial inflammation is an important pathogenetic factor in systemic arterial micro-calcification development.

Connected care for endocarditis and heart failure patients: a hospital-at-home programme.

BACKGROUND: Healthcare expenditure in the Netherlands is increasing at such a rate that currently 1 in 7 employees are working in healthcare/curative care. Future increases in healthcare spending will be restricted, given that 10% of the country's gross domestic product is spent on healthcare and the fact that there is a workforce shortage. Dutch healthcare consists of a curative sector (mostly hospitals) and nursing care at home. The two entities have separate national budgets (€25 bn + €20 bn respectively) AIM: In a proof of concept, we explored a new hospital-at-home model combining hospital cure and nursing home care budgets. This study tests the feasibility of (1) providing hospital care at home, (2) combining financial budgets, (3) increasing workforces by combining teams and (4) improving perspectives and increasing patient and staff satisfaction. RESULTS: We tested the feasibility of combining the budgets of a teaching hospital and home care group for cardiology. The budgets were sufficient to hire three nurse practitioners who were trained to work together with 12 home care cardiovascular nurses to provide care in a hospital-at-home setting, including intravenous treatment. Subsequently, the hospital-at-home programme for endocarditis and heart failure treatment was developed and a virtual ward was built within the e­patient record. CONCLUSION: The current model demonstrates a proof of concept for a hospital-at-home programme providing hospital-level curative care at home by merging hospital and home care nursing staff and budgets. From the clinical perspective, ambulatory intravenous antibiotic and diuretic treatment at home was effective in safely achieving a reduced length of stay of 847 days in endocarditis patients and 201 days in heart-failure-at-home patients. We call for further studies to facilitate combined home care and hospital cure budgets in cardiology to confirm this concept.

Rationale and design of the OPTIMIZE trial: OPen label multicenter randomized trial comparing standard IMmunosuppression with tacrolimus and mycophenolate mofetil with a low exposure tacrolimus regimen In combination with everolimus in de novo renal transplantation in Elderly patients.

BACKGROUND: In 2019, more than 30 % of all newly transplanted kidney transplant recipients in The Netherlands were above 65 years of age. Elderly patients are less prone to rejection, and death censored graft loss is less frequent compared to younger recipients. Elderly recipients do have increased rates of malignancy and infection-related mortality. Poor kidney transplant function in elderly recipients may be related to both pre-existing (i.e. donor-derived) kidney damage and increased susceptibility to nephrotoxicity of calcineurin inhibitors (CNIs) in kidneys from older donors. Hence, it is pivotal to shift the focus from prevention of rejection to preservation of graft function and prevention of over-immunosuppression in the elderly. The OPTIMIZE study will test the hypothesis that reduced CNI exposure in combination with everolimus will lead to better kidney transplant function, a reduced incidence of complications and improved health-related quality of life for kidney transplant recipients aged 65 years and older, compared to standard immunosuppression. METHODS: This open label, randomized, multicenter clinical trial will include 374 elderly kidney transplant recipients (≥ 65 years) and consists of two strata. Stratum A includes elderly recipients of a kidney from an elderly deceased donor and stratum B includes elderly recipients of a kidney from a living donor or from a deceased donor < 65 years. In each stratum, subjects will be randomized to a standard, tacrolimus-based immunosuppressive regimen with mycophenolate mofetil and glucocorticoids or an adapted immunosuppressive regimen with reduced CNI exposure in combination with everolimus and glucocorticoids. The primary endpoint is 'successful transplantation', defined as survival with a functioning graft and an eGFR ≥ 30 ml/min per 1.73 m2 in stratum A and ≥ 45 ml/min per 1.73 m2 in stratum B, after 2 years, respectively. CONCLUSIONS: The OPTIMIZE study will help to determine the optimal immunosuppressive regimen after kidney transplantation for elderly patients and the cost-effectiveness of this regimen. It will also provide deeper insight into immunosenescence and both subjective and objective outcomes after kidney transplantation in elderly recipients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03797196 , registered January 9th, 2019. EudraCT: 2018-003194-10, registered March 19th, 2019.

[The development of an mHealth app with young people in mental health care using Agile; a practical experiment]. / Agile ontwikkelen van een m-healthapp met jongeren in de ggz: een praktijk-experiment.

BACKGROUND: In recent years, many mobile health (mHealth) apps have been developed to support diagnostics and treatment, among other purposes. It is likely that involving patients closely in the development process will lead to more relevant apps. In theory, the Agile style of software development can make this possible. However, whether this is feasible in mental healthcare practice has never been investigated.
AIM: To investigate whether it is possible in practice to develop an mHealth app together with young people in a highly specialized mental healthcare context, by using Agile.
METHOD: A proof-of-concept study that seeks to develop an mHealth app by implementing Agile together with clinically admitted, young psychiatric patients. Patients would directly influence the development goals and priorities.
RESULTS: In the period from May to July 2019 the app 'Constant Circles' has been developed using Agile together with patients. The main focus of this app is social support. The patients supplied 18 concrete user stories and also provided feedback with general principles for developing an mHealth app.
CONCLUSION: This study has demonstrated that it is possible to closely involve patients in highly specialized mental health care in the development process of an mHealth app by using Agile.

18F-sodium fluoride positron emission tomography assessed microcalcifications in culprit and non-culprit human carotid plaques.

BACKGROUND: 18F-NaF positron emission tomography (PET) targets microcalcifications. We compared in vitro microPET assessed 18F-NaF uptake between culprit and non-culprit human carotid plaques. Furthermore, we compared 18F-NaF uptake with calcification visualized on microcomputed tomography (microCT). METHODS: Carotid plaques from stroke patients undergoing surgery were incubated in 18F-NaF and scanned using a microPET and a microCT scan. The average PET assessed 18F-NaF uptake was expressed as percentage of the incubation dose per gram (%Inc/g). 18F-NaF PET volume of interest (VOI) was compared with CT calcification VOI. RESULTS: 23 carotid plaques (17 culprit, 6 non-culprit) were included. The average 18F-NaF uptake in culprit carotid plaques was comparable with the uptake in non-culprit carotid plaques (median 2.32 %Inc/g [IQR 1.98 to 2.81] vs. median 2.35 %Inc/g [IQR 1.77 to 3.00], P = 0.916). Only a median of 10% (IQR 4 to 25) of CT calcification VOI showed increased 18F-NaF uptake, while merely a median of 35% (IQR 6 to 42) of 18F-NaF PET VOI showed calcification on CT. CONCLUSIONS: 18F-NaF PET represents a different stage in the calcification process than CT. We observed a similar PET assessed 18F-NaF uptake and pattern in culprit and non-culprit plaques of high-risk patients, indicating that this method may be of more value in early atherosclerotic stenosis development.

Ten-year results of the PORTEC-2 trial for high-intermediate risk endometrial carcinoma: improving patient selection for adjuvant therapy.

BACKGROUND: PORTEC-2 was a randomised trial for women with high-intermediate risk (HIR) endometrial cancer, comparing pelvic external beam radiotherapy (EBRT) with vaginal brachytherapy (VBT). We evaluated long-term outcomes combined with the results of pathology review and molecular analysis. METHODS: 427 women with HIR endometrial cancer were randomised between 2002-2006 to VBT or EBRT. Primary endpoint was vaginal recurrence (VR). Pathology review was done in 97.4%, combined with molecular analysis. RESULTS: Median follow-up was 116 months; 10-year VR was 3.4% versus 2.4% for VBT vs. EBRT (p = 0.55). Ten-year pelvic recurrence (PR) was more frequent in the VBT group (6.3% vs. 0.9%, p = 0.004), mostly combined with distant metastases (DM). Ten-year isolated PR was 2.5% vs. 0.5%, p = 0.10, and DM 10.4 vs. 8.9% (p = 0.45). Overall survival for VBT vs. EBRT was 69.5% vs. 67.6% at 10 years (p = 0.72). L1CAM and p53-mutant expression and substantial lymph-vascular space invasion were risk factors for PR and DM. EBRT reduced PR in cases with these risk factors. CONCLUSION: Long-term results of the PORTEC-2 trial confirm VBT as standard adjuvant treatment for HIR endometrial cancer. Molecular risk assessment has the potential to guide adjuvant therapy. EBRT provided better pelvic control in patients with unfavourable risk factors.

Clinical consequences of upfront pathology review in the randomised PORTEC-3 trial for high-risk endometrial cancer.

Background: In the PORTEC-3 trial, women with high-risk endometrial cancer (HR-EC) were randomised to receive pelvic radiotherapy (RT) with or without concurrent and adjuvant chemotherapy (two cycles of cisplatin 50 mg/m2 in weeks 1 and 4 of RT, followed by four cycles of carboplatin AUC5 and paclitaxel 175 mg/m2). Pathology review was required before patient enrolment. The aim of this analysis was to evaluate the role of central pathology review before randomisation. Patients and methods: A total of 1295 cases underwent pathology review to confirm HR-EC in the Netherlands (n = 395) and the UK (n = 900), and for 1226/1295 (95%) matching review and original reports were available. In total, 329 of these patients were enrolled in the PORTEC-3 trial: 145 in the Netherlands and 184 in the UK, comprising 48% of the total PORTEC-3 cohort of 686 participants. Areas of discrepancies were evaluated, and inter-observer agreement between original and review opinion was evaluated by calculating the kappa value (κ). Results: In the 1226 pathology reviews, 6356 selected items were evaluable for both original and review pathology. In 43% of cases at least one pathology item changed after review. For 102 patients (8%), this discrepancy led to ineligibility for the PORTEC-3 trial, most frequently due to differences in the assessment of histological type (34%), endocervical stromal involvement (27%) and histological grade (19%). Lowest inter-observer agreement was found for histological type (κ = 0.72), lymph-vascular space invasion (κ = 0.72) and histological grade (κ = 0.70). Conclusion: Central pathology review by expert gynaeco-pathologists changed histological type, grade or other items in 43% of women with HR-EC, leading to ineligibility for the PORTEC-3 trial in 8%. Upfront pathology review is essential to ensure enrolment of the target trial-population, and to avoid over- or undertreatment, especially when treatment modalities with substantial toxicity are involved. This study is registered with ISRCTN (ISRCTN14387080, www.controlled-trials.com) and with ClinicalTrials.gov (NCT00411138).

A glycerophospholipid-specific pocket in the RVFV class II fusion protein drives target membrane insertion.

The Rift Valley fever virus (RVFV) is transmitted by infected mosquitoes, causing severe disease in humans and livestock across Africa. We determined the x-ray structure of the RVFV class II fusion protein Gc in its postfusion form and in complex with a glycerophospholipid (GPL) bound in a conserved cavity next to the fusion loop. Site-directed mutagenesis and molecular dynamics simulations further revealed a built-in motif allowing en bloc insertion of the fusion loop into membranes, making few nonpolar side-chain interactions with the aliphatic moiety and multiple polar interactions with lipid head groups upon membrane restructuring. The GPL head-group recognition pocket is conserved in the fusion proteins of other arthropod-borne viruses, such as Zika and chikungunya viruses, which have recently caused major epidemics worldwide.

How to define the hemodynamic significance of an equivocal iliofemoral artery stenosis: Review of literature and outcomes of an international questionnaire.

Purpose The goal of the study was to review current literature regarding the diagnosis of equivocal (50-70%) iliofemoral artery stenosis and compare these findings with the daily practice of an international panel of endovascular experts. Methods The Medline Database was searched for relevant publications, and an electronic survey was sent to experts in the field covering the following topics: definition of an equivocal iliofemoral artery stenosis, angiographic visualization and investigation protocols of an equivocal stenosis, intra-arterial pressure measurements, and definition of hemodynamic significance of an equivocal iliofemoral artery stenosis using a physiologic measure. Results Of the 37 invited endovascular experts, 21 (53.8%) agreed to participate in the survey. Analysis of existing literature shows that the level of evidence for diagnosing equivocal iliofemoral artery stenosis is mediocre and is not being implemented by experts in the field. Conclusion Studies have shown that a stenosis of between 50% and 70% iliofemoral lumen diameter reduction shows a wide range of trans-stenotic pressure gradients. Equivocal iliofemoral artery stenosis can best be identified using three-dimensional quantitative vascular analysis software. Although evidence for a clear hemodynamic cutoff point is weak, performing trans-lesion intra-arterial pressure measurements at rest and during maximal hyperemia is preferred. Diagnosing iliofemoral artery stenosis solely on lumen diameter reduction is inadequate.

Isoform specific differences in phospholipase C beta 1 expression in the prefrontal cortex in schizophrenia and suicide.

Our previous study demonstrated that phospholipase C beta 1 mRNA was down-regulated in Brodmann's area 46 from subjects with schizophrenia. However, phospholipase C beta 1 protein has also been shown to be lower in Brodmann's area 8 and 9 from teenage suicide subjects, creating a potential confound in interpreting the findings in schizophrenia due to the high suicide rate associated with this disorder. To begin to reconcile and consolidate these findings, in this study, we measured mRNA and protein levels of phospholipase C beta 1 variants a and b in Brodmann's area 46 and Brodmann's area 9 from subjects with schizophrenia, many of whom were suicide completers, and determined the diagnostic specificity of observed findings. Consistent with our previous study, levels of phospholipase C beta 1 a and b mRNA, but not protein, were lower in Brodmann's area 46 from subjects with schizophrenia. In Brodmann's area 9, phospholipase C beta 1a protein levels were lower in subjects with schizophrenia, while phospholipase C beta 1b mRNA was higher and protein was lower in those that had died of suicide. Altered protein levels in Brodmann's area 9 appeared to be diagnostically specific, as we did not detect these changes in subjects with bipolar disorder, major depressive disorder or suicide completers with no diagnosis of mental illness. We further assessed the relationship between phospholipase C beta 1 and levels of muscarinic receptors (CHRMs) that signal through this protein, in both human and Chrm knockout mouse central nervous system tissue, and found no strong relationship between the two. Understanding central nervous system differences in downstream effector pathways in schizophrenia may lead to improved treatment strategies and help to identify those at risk of suicide.

Social stress models in rodents: Towards enhanced validity.

Understanding the role of the social environment in the development of stress related diseases requires a more fundamental understanding of stress. Stress includes not only the stimulus and the response but also the individual appraisal of the situation. The social environment is not only essential for survival it is at the same time an important source of stressors. This review discusses the social stress concept, how it has been studied in rodents in the course of time and some more recent insights into the appraisal process. In addition to the factors controllability and predictability, outcome expectancy and feedback of the victim's own actions during the social stress are suggested to be important factors in the development of stress related disease. It is hypothesized that individual differences in the way in which these factors are used in the appraisal of everyday life situations may explain individual vulnerability.

[How do adolescent inpatients experience seclusion and other coercive measures?]. / Hoe beleven opgenomen adolescenten separatie en andere vormen van dwang?

BACKGROUND: The reduction of coercive measures in psychiatry, particularly of seclusion, is considered to be a matter of some urgency. When policy changes with regard to coercive measures are being considered, the wishes and preferences of patients should be taken into account. Up till now, however, there have not been any studies that have examined how adolescent inpatients feel about coercive measures. AIM: To examine the way adolescent inpatients feel about seclusion and other forms of coercive measures. METHOD: Adolescent inpatients in a Dutch centre for orthopsychiatry (n = 34) were asked about their experiences with and their thoughts on coercive measures in general and on seclusion in particular. RESULTS: Thirty-two respondents took part. More than half of the 18 adolescents who had had prior experiences of coercive measures preferred seclusion to involuntary medication. CONCLUSION: Policy-makers who want to reduce coercive measures in psychiatry should not focus primarily on the reduction of seclusion. Patient preferences, which vary depending on the nature of the patient population, need to be considered carefully and taken into account.

Screening of a Library of FDA-Approved Drugs Identifies Several Enterovirus Replication Inhibitors That Target Viral Protein 2C.

Enteroviruses (EVs) represent many important pathogens of humans. Unfortunately, no antiviral compounds currently exist to treat infections with these viruses. We screened the Prestwick Chemical Library, a library of approved drugs, for inhibitors of coxsackievirus B3, identified pirlindole as a potent novel inhibitor, and confirmed the inhibitory action of dibucaine, zuclopenthixol, fluoxetine, and formoterol. Upon testing of viruses of several EV species, we found that dibucaine and pirlindole inhibited EV-B and EV-D and that dibucaine also inhibited EV-A, but none of them inhibited EV-C or rhinoviruses (RVs). In contrast, formoterol inhibited all enteroviruses and rhinoviruses tested. All compounds acted through the inhibition of genome replication. Mutations in the coding sequence of the coxsackievirus B3 (CV-B3) 2C protein conferred resistance to dibucaine, pirlindole, and zuclopenthixol but not formoterol, suggesting that 2C is the target for this set of compounds. Importantly, dibucaine bound to CV-B3 protein 2C in vitro, whereas binding to a 2C protein carrying the resistance mutations was reduced, providing an explanation for how resistance is acquired.

An undetected common renal arterial trunk: surgical consequences and morbidity analysis.

We present a patient with a recurrent precaval left renal artery, stemming from a right-sided common trunk renal artery. The patient was a 44-year male who presented with a post-traumatic grade IV renal injury. After 3 months without renal function improvement and repeated urinary tract infection, a laparoscopic nephrectomy of the affected right kidney was performed, without upfront identification of the vascular variation, resulting in ischemia of the remaining left kidney. An anastomosis of the common renal trunk and the distal left renal artery was created in between the abdominal aorta and the inferior vena cava. This case describes the importance of upfront detection of renal vascular variations using the appropriate imaging techniques.

The neurobiology of offensive aggression: Revealing a modular view.

Experimental studies aimed at understanding the neurobiology of aggression started in the early 20th century, and by employing increasingly sophisticated tools of functional neuroanatomy (i.e., from electric/chemical lesion and stimulation techniques to neurochemical mapping and manipulations) have provided the important framework for the functional brain circuit organization of aggressive behaviors. Recently, newly emerging technologies for mapping,measuring and manipulating neural circuitry at the level of molecular and genetically defined neuronal subtypes promise to further delineate the precise neural microcircuits mediating the initiation and termination of aggressive behavior, and characterize its dynamic neuromolecular functioning. This paper will review some of the behavioral, neuroanatomical and neurochemical evidence in support of a modular view of the neurobiology of offensive aggressive behavior. Although aggressive behavior likely arises from a specific concerted activity within a distributed neural network across multiple brain regions, emerging opto- and pharmacogenetic neuronal manipulation studies make it clear that manipulation of molecularly-defined neurons within a single node of this global interconnected network seems to be both necessary and sufficient to evoke aggressive attacks. However, the evidence so far also indicates that in addition to behavior-specific neurons there are neuronal systems that should be considered as more general behavioral control modules. The answer to the question of behavioral specificity of brain structures at the level of individual neurons requires a change of the traditional experimental setup. Studies using c-fos expression mapping usually compare the activation patterns induced by for example aggression with a home cage control. However, to reveal the behavioral specificity of this neuronal activation pattern, a comparison with other social and non-social related behaviors such as mating, defensive burying or running might be more appropriate. In addition, the correlations between aggressive behavior and other behaviors in different environmental contexts might give an indication of these more general behavioral control functions. Elucidating how neural circuits that modulate social-aggressive behavior also mediate other complex emotional behaviors or states will lead to a better understanding of the molecular mechanisms by which social deficits are expressed in various neuropsychiatric disorders. This likely will lead to more efficacious pharmacological or circuit-based therapeutics to curb excessive/abnormal aggressive behavior and improve social function.

Evaluation of the diagnostic work-up in children with myocarditis and idiopathic dilated cardiomyopathy.

The underlying etiology of dilated cardiomyopathy (DCM) in children varies, 14-22% is secondary to myocarditis, and the majority remains idiopathic. Etiology has prognostic value; however, 'a clinical diagnosis of myocarditis' has been frequently used because the gold standard [endomyocardial biopsy (EMB)] is often not performed. Therefore, a consistent diagnostic approach and interpretation is needed. In this multicenter study, we evaluated the diagnostic approach and interpretation of the viral results in children with myocarditis and idiopathic DCM. We included 150 children with DCM, of whom 103 were assigned the diagnosis myocarditis (n = 21) or idiopathic DCM (n = 82) by the attending physician. Viral tests were performed in 97/103 patients, in only 34% (n = 35) some of the tests were positive. Of those patients, we evaluated the probability of the assigned diagnosis using the viral test results. We classified viral test results as reflecting definite or probable myocarditis in 14 children and possible or unlikely myocarditis in 21 children. Based on this classification, 23% of patients were misclassified. We found that in children with DCM, the diagnostic approach varied and the interpretation was mainly based on viral results. Since a 'clinical diagnosis of myocarditis' has been frequently used in daily practice because of the lack of EMB results, a uniform protocol is needed. We propose to use viral test results in several steps (blood PCR, serology, PCR and/or cultures of the gastro-intestinal and respiratory tract, and EMB results) to estimate the probability of myocarditis.

Ventilator setting in ICUs: comparing a Dutch with a European cohort.

BACKGROUND: From data collected during the third International Study on Mechanical Ventilation (ISMV), we compared data from a Dutch cohort with a European cohort. We hypothesised that tidal volumes were smaller and applied positive end-expiratory pressure (PEEP) was higher in the Netherlands, compared with the European cohort. We also compared use of non-invasive ventilation (NIV) and outcomes in both cohorts. METHODS: A post-hoc analysis of a prospective observational study of patients receiving mechanical ventilation. RESULTS: Tidal volumes were smaller (7.6 vs. 8.1 ml÷kg predicted bodyweight) in the Dutch cohort and applied PEEP was higher (8 vs. 6 cm H2O). Fewer patients admitted in the Netherlands received NIV as first mode of mechanical ventilation (7.1 vs. 16.7%). Fewer patients in the Dutch cohort developed an ICU-acquired pneumonia (4.5 vs. 12.3%, p < 0.01) and sepsis (5.7 vs. 10.9%, p = 0.03), but more patients were diagnosed as having delirium (15.8 vs. 4.6%, p < 0.01). ICU and in-hospital mortality rates were 19% and 25%, respectively, in Dutch ICUs vs. 26% and 33% in Europe (p = 0.06 and 0.03). CONCLUSION: Tidal volumes were smaller and applied PEEP was higher in the Dutch cohort compared with international data, but both Dutch and international patients received larger tidal volumes than recommended for prevention or treatment of acute respiratory distress syndrome. NIV as first mode of mechanical ventilation is less commonly used in the Netherlands. The incidence of ICU-acquired pneumonia is lower and of delirium higher in the Netherlands compared with international data.

Mast cell leukaemia presenting with multiple osteoporotic fractures in an elderly woman.

Osteoporotic fractures in elderly women are mainly due to postmenopausal bone loss but can sometimes be caused by a disabling haematological disease. We describe an 84-year-old woman suffering from multiple osteoporotic fractures as a manifestation of mast cell leukaemia. Mast cell leukaemia is a rare form of systemic mastocytosis with a poor prognosis and very few therapeutic options. Osteoporotic fractures have seldom been reported as its initial manifestation.