Rogier Donders

Development and validation of PRE-DELIRIC (PREdiction of DELIRium in ICu patients) delirium prediction model for intensive care patients: observational multicentre study

Objectives To develop and validate a delirium prediction model for adult intensive care patients and determine its additional value compared with prediction by caregivers. Design Observational multicentre study. Setting Five intensive care units in the Netherlands (two university hospitals and three university affiliated teaching hospitals). Participants 3056 intensive care patients aged 18 years or over. Main outcome measure Development of delirium (defined as at least one positive delirium screening) during patients’ stay in intensive care. Results The model was developed using 1613 consecutive intensive care patients in one hospital and temporally validated using 549 patients from the same hospital. For external validation, data were collected from 894 patients in four other hospitals. The prediction (PRE-DELIRIC) model contains 10 risk factors—age, APACHE-II score, admission group, coma, infection, metabolic acidosis, use of sedatives and morphine, urea concentration, and urgent admission. The model had an area under the receiver operating characteristics curve of 0.87 (95% confidence interval 0.85 to 0.89) and 0.86 after bootstrapping. Temporal validation and external validation resulted in areas under the curve of 0.89 (0.86 to 0.92) and 0.84 (0.82 to 0.87). The pooled area under the receiver operating characteristics curve (n=3056) was 0.85 (0.84 to 0.87). The area under the curve for nurses’ and physicians’ predictions (n=124) was significantly lower at 0.59 (0.49 to 0.70) for both. Conclusion The PRE-DELIRIC model for intensive care patients consists of 10 risk factors that are readily available within 24 hours after intensive care admission and has a high predictive value. Clinical prediction by nurses and physicians performed significantly worse. The model allows for early prediction of delirium and initiation of preventive measures. Trial registration Clinical trials NCT00604773 (development study) and NCT00961389 (validation study).

Increasingly strong reduction in breast cancer mortality due to screening

Background:Favourable outcomes of breast cancer screening trials in the 1970s and 1980s resulted in the launch of population-based service screening programmes in many Western countries. We investigated whether improvements in mammography and treatment modalities have had an influence on the effectiveness of breast cancer screening from 1975 to 2008.Methods:In Nijmegen, the Netherlands, 55 529 women received an invitation for screening between 1975 and 2008. We designed a case–referent study to evaluate the impact of mammographic screening on breast cancer mortality over time from 1975 to 2008. A total number of 282 breast cancer deaths were identified, and 1410 referents aged 50–69 were sampled from the population invited for screening. We estimated the effectiveness by calculating the odds ratio (OR) indicating the breast cancer death rate for screened vs unscreened women.Results:The breast cancer death rate in the screened group over the complete period was 35% lower than in the unscreened group (OR=0.65; 95% CI=0.49–0.87). Analysis by calendar year showed an increasing effectiveness from a 28% reduction in breast cancer mortality in the period 1975–1991 (OR=0.72; 95% CI=0.47–1.09) to 65% in the period 1992–2008 (OR=0.35; 95% CI=0.19–0.64).Conclusion:Our results show an increasingly strong reduction in breast cancer mortality over time because of mammographic screening.

Tailored cognitive-behavioral therapy and exercise training for high-risk patients with fibromyalgia.

The treatment of patients with fibromyalgia (FM), a high‐prevalence chronic pain condition with a high impact on both patients and society, poses a great challenge to clinicians due to a lack of effective treatments. In view of the large individual variability in outcome, selecting patients at risk of long‐term dysfunction and offering tailored treatment may be promising for beneficial treatment effects.

Improving person-centred care in nursing homes through dementia-care mapping: design of a cluster-randomised controlled trial.

BackgroundThe effectiveness and efficiency of nursing-home dementia care are suboptimal: there are high rates of neuropsychiatric symptoms among the residents and work-related stress among the staff. Dementia-care mapping is a person-centred care method that may alleviate both the resident and the staff problems. The main objective of this study is to evaluate the effectiveness and cost-effectiveness of dementia-care mapping in nursing-home dementia care.Methods/DesignThe study is a cluster-randomised controlled trial, with nursing homes grouped in clusters. Studywise minimisation is the allocation method. Nursing homes in the intervention group will receive a dementia-care-mapping intervention, while the control group will receive usual care. The primary outcome measure is resident agitation, to be assessed with the Cohen-Mansfield Agitation Inventory. The secondary outcomes are resident neuropsychiatric symptoms, assessed with the Neuropsychiatric Inventory - Nursing Homes and quality of life, assessed with Qualidem and the EQ-5D. The staff outcomes are stress reactions, job satisfaction and job-stress-related absenteeism, and staff turnover rate, assessed with the Questionnaire about Experience and Assessment of Work, the General Health Questionnaire-12, and the Maastricht Job Satisfaction Scale for Health Care, respectively. We will collect the data from the questionnaires and electronic registration systems. We will employ linear mixed-effect models and cost-effectiveness analyses to evaluate the outcomes. We will use structural equation modelling in the secondary analysis to evaluate the plausibility of a theoretical model regarding the effectiveness of the dementia-care mapping intervention. We will set up process analyses, including focus groups with staff, to determine the relevant facilitators of and barriers to implementing dementia-care mapping broadly.DiscussionA novelty of dementia-care mapping is that it offers an integral person-centred approach to dementia care in nursing homes. The major strengths of the study design are the large sample size, the cluster-randomisation, and the one-year follow-up. The generalisability of the implementation strategies may be questionable because the motivation for person-centred care in both the intervention and control nursing homes is above average. The results of this study may be useful in improving the quality of care and are relevant for policymakers.Trial registrationThe trial is registered in the Netherlands National Trial Register: NTR2314.

Circulating DNA is a non-invasive prognostic factor for survival in non-small cell lung cancer.

INTRODUCTION Circulating plasma DNA is present in a considerably higher concentration in lung cancer patients than in controls. Conflicting data are reported about circulating DNA as a prognostic factor. The aim of this study was to prospectively analyse the relationship of circulating plasma DNA with overall survival (OS) of previously untreated non-small cell lung cancer (NSCLC) patients. METHODS 46 untreated NSCLC patients and 21 controls with a follow-up time of 6.5 years were analyzed. Quantification of baseline circulating plasma DNA was performed by a real-time quantitative polymerase chain reaction (qPCR) targeting the human beta-globin gene. Survival analysis was performed using the Kaplan-Meier method and compared with a Cox-regression analysis. RESULTS The median DNA concentration of the patients who died (87%) was significantly higher compared to the patients that survived at the end of follow-up (55ng/ml versus 23ng/ml, p=0.02). In patients with higher DNA concentration overall survival was significantly worse. In this study no relation of DNA concentration with tumour characteristics, age, gender or pulmonary inflammatory conditions was found. CONCLUSION In this study a high circulating plasma DNA concentration at time of diagnosis in NSCLC patients was a prognostic factor for poorer survival. Circulating DNA may be used as a non-invasive biomarker to refine the prognostic profile in NSCLC patients.

Isoniazid, Rifampin, and Pyrazinamide Plasma Concentrations in Relation to Treatment Response in Indonesian Pulmonary Tuberculosis Patients

ABSTRACT Numerous studies have reported low concentrations of antituberculosis drugs in tuberculosis (TB) patients, but few studies have examined whether low drug concentrations affect TB treatment response. We examined steady-state plasma concentrations of isoniazid, rifampin, and pyrazinamide at 2 h after the administration of drugs (C2 h) among 181 patients with pulmonary tuberculosis in Indonesia and related these to bacteriological response during treatment. C2 h values below reference values for either isoniazid, rifampin, or pyrazinamide were found in 91% of patients; 60% had at least two low C2 h concentrations. The isoniazid C2 h was noticeably lower in fast versus slow acetylators (0.9 mg/liter versus 2.2 mg/liter, P < 0.001). At the end of treatment, 82% of the patients were cured, whereas 30 patients (17%) had dropped out during the study, and 2 patients (1%) failed treatment. No association was found between C2 h concentrations and sputum culture results at 8 weeks of treatment. Post hoc analysis showed that patients with low pyrazinamide C2 h (P = 0.01) and patients with large extensive lung lesions (P = 0.01) were at risk of at least one positive culture at week 4, 8, or 24/32. Antituberculosis drug concentrations were often low, but treatment response was nevertheless good. No association was found between drug concentrations and 8 weeks culture conversion, but low pyrazinamide drug concentrations may be associated with a less favorable bacteriological response. The use of higher doses of pyrazinamide may warrant further investigation.

Plasma from septic shock patients induces loss of muscle protein

IntroductionICU-acquired muscle weakness commonly occurs in patients with septic shock and is associated with poor outcome. Although atrophy is known to be involved, it is unclear whether ligands in plasma from these patients are responsible for initiating degradation of muscle proteins. The aim of the present study was to investigate if plasma from septic shock patients induces skeletal muscle atrophy and to examine the time course of plasma-induced muscle atrophy during ICU stay.MethodsPlasma was derived from septic shock patients within 24 hours after hospital admission (n = 21) and healthy controls (n = 12). From nine patients with septic shock plasma was additionally derived at two, five and seven days after ICU admission. These plasma samples were added to skeletal myotubes, cultured from murine myoblasts. After incubation for 24 hours, myotubes were harvested and analyzed on myosin content, mRNA expression of E3-ligase and Nuclear Factor Kappa B (NFκB) activity. Plasma samples were analyzed on cytokine concentrations.ResultsMyosin content was approximately 25% lower in myotubes exposed to plasma from septic shock patients than in myotubes exposed to plasma from controls (P < 0.01). Furthermore, patient plasma increased expression of E3-ligases Muscle RING Finger protein-1 (MuRF-1) and Muscle Atrophy F-box protein (MAFbx) (P < 0.01), enhanced NFκB activity (P < 0.05) and elevated levels of ubiquitinated myosin in myotubes. Myosin loss was significantly associated with elevated plasma levels of interleukin (IL)-6 in septic shock patients (P < 0.001). Addition of antiIL-6 to septic shock plasma diminished the loss of myosin in exposed myotubes by approximately 25% (P < 0.05). Patient plasma obtained later during ICU stay did not significantly reduce myosin content compared to controls.ConclusionsPlasma from patients with septic shock induces loss of myosin and activates key regulators of proteolysis in skeletal myotubes. IL-6 is an important player in sepsis-induced muscle atrophy in this model. The potential to induce atrophy is strongest in plasma obtained during the early phase of human sepsis.

The evidence provided by a single trial is less reliable than its statistical analysis suggests

OBJECTIVE To investigate whether a single trial can provide sufficiently robust evidence to warrant clinical implementation of its results. Trial-specific factors, such as subject selection, study design, and execution strategy, have an impact on the outcome of trials. In multiple trials, they may lead to heterogeneity that can be taken into account in the (random effects) meta-analysis. Single trials lack this method of estimating the impact of such factors, and this affects the credibility of the results. STUDY DESIGN AND SETTING To indicate how much the precision of the results of a single trial might be overestimated, we calculated the ratio of the widths of the confidence intervals when heterogeneity was taken into account and when it was not. RESULTS The ratios of the widths of the confidence intervals with and without between-study variability were 1.15, 1.41, and 2.00, when the heterogeneity I(2) values were 0.25, 0.50, and 0.75, respectively. CONCLUSION The results of a single trial should be interpreted with caution. When it is difficult to predict or determine how trial-specific factors influence the results, the best way to evaluate the performance of a treatment is to use multiple, possibly smaller, trials.

Pharmacokinetic/pharmacodynamic analysis of an intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis

Recent data suggest that intensified antimicrobial treatment may improve the outcome of tuberculous meningitis (TBM). Considering that drug exposure is the intermediate link between dose and effect, we examined the concentration-response relationship for rifampicin and moxifloxacin in TBM patients. In an open-label, phase 2 clinical trial performed in Indonesia (ClinicalTrials.gov NCT01158755), 60 TBM patients were randomised to receive standard-dose (450mg oral) or high-dose rifampicin (600mg intravenous) plus either oral moxifloxacin (400mg or 800mg) or ethambutol (750mg). After 14 days, all patients continued with standard tuberculosis treatment. Pharmacokinetic sampling was performed once in every patient during the first three critical days. Differences in exposure between patients who died or survived were tested with independent samples t-tests. The relationship between drug exposure and mortality was examined using Cox regression. Compared with patients who died during the 2 weeks of intensified treatment, surviving patients had significantly higher rifampicin plasma AUC0-6h, plasma Cmax and CSF Chighest. Additionally, patients had a 32-43% lower relative likelihood of dying with an interquartile range increase in rifampicin exposure. Moxifloxacin exposure did not show a clear relationship with survival. From exposure-response curves, a rifampicin plasma AUC0-6h of ∼70mg·h/L (AUC0-24h of ∼116mgh/L) and a Cmax of ∼22mg/L were deduced as minimum target values for treatment. A strong concentration-effect relationship was found, with higher rifampicin exposure leading to better TBM survival. The current treatment dose of rifampicin is suboptimal; higher doses of rifampicin should be evaluated.

Development of early communication skills in the first two years of life

The first two years of life is a crucially important period for the development of communication skills. In this study joint attention and language development were monthly assessed between 8 and 24 months of age in a sample of 23 typically developing children to establish the developmental trajectory of specific joint attention skills, to investigate the developmental interrelations of these different joint attention skills with vocabulary size, and to examine whether the order of development of following and directing attention influences the development of other early communication skills such as language. All joint attention skills emerged between 8 and 15 months of age and responsive joint attention skills tend to emerge before initiative joint attention. Early joint attention skills influenced later language development, but not the other way around. Children in whom directing attention with gaze alternation developed early (in age or order) showed a relatively larger early vocabulary growth. A fine grained mapping of the normal development of early communication skills can be helpful in the early detection of abnormalities in these skills.