To treat or not to treat : Biomarker-guided therapy for febrile patients in the emergency department

The overall aims of this thesis were to investigate if biomarkers can improve early identification of bacterial infections and provide early estimation of severity of disease, and if biomarkers can be used to effectively reduce the prescription of antibiotics for febrile patients without bacterial infections in the ED

Process improvement in healthcare: Overall resource efficiency

This paper aims to develop a unifying and quantitative conceptual framework for healthcare processes from the viewpoint of process improvement. The work adapts standard models from operation management to the specifics of healthcare processes. We propose concepts for organizational modeling of healthcare processes, breaking down work into micro processes, tasks, and resources. In addition, we propose an axiological model which breaks down general performance goals into process metrics. The connexion between both types of models is made explicit as a system of metrics for process flow and resource efficiency. The conceptual models offer exemplars for practical support in process improvement efforts, suggesting to project leaders how to make a diagrammatic representation of a process, which data to gather, and how to analyze and diagnose a process's flow and resource utilization. The proposed methodology links on to process improvement methodologies such as business process reengineering, six sigma, lean thinking, theory of constraints, and total quality management. In these approaches, opportunities for process improvement are identified from a diagnosis of the process under study. By providing conceptual models and practical templates for process diagnosis, the framework relates many disconnected strands of research and application in process improvement in healthcare to the unifying pursuit of process improvement

Psychological risk factors and the course of depression and anxiety disorders:A review of 15 years NESDA research

Background: The Netherlands Study of Depression and Anxiety (NESDA; Nbaseline=2981) is an ongoing longitudinal, multi-site, naturalistic, cohort study examining the etiology, course, and consequences of depression and anxiety. In this article we synthesize and evaluate fifteen years of NESDA research on prominent psychological risk factors for the onset, persistence, recurrence, and comorbidity of affective disorders.Methods: A narrative review of 62 NESDA articles examining the specificity and predictive value of neuroticism, behavioral inhibition, repetitive negative thinking, experiential avoidance, cognitive reactivity, locus of control, (implicit) self-esteem, (implicit) disorder-specific self-associations, and attentional bias for the course of affective disorders.Results: All self-reported risk factors showed cross-sectional relationships with singular and comorbid affective disorders, and prospective relationships with the development and chronicity of depression and anxiety disorders. High neuroticism, low self-esteem, and negative repetitive thinking showed most prominent transdiagnostic relationships, whereas cognitive reactivity showed most pronounced depression-specific associations. Implicit self-esteem showed predictive validity for the persistence and recurrence of anxiety and depression over and above self-reported risk factors. Automatic approach-avoidance behavior and attentional bias for negative, positive, or threat words showed no relationship with affective disorders.Conclusion: NESDA identified both (a) transdiagnostic factors (e.g., neuroticism, low implicit self-esteem, repetitive negative thinking) that may help explain the comorbidity between affective disorders and overlap in symptoms, and (b) indications for disorder-specific risk factors (e.g., cognitive responsivity) which support the relevance of distinct disorder categories and disorder-specific mechanisms. Thus, the results point to the relevance of both transdiagnostic and disorder-specific targets for therapeutic interventions.Stress-related psychiatric disorders across the life spa

Acute cigarette smoke exposure leads to higher viral infection in human bronchial epithelial cultures by altering interferon, glycolysis and GDF15-related pathways

Background Acute exacerbations of chronic inflammatory lung diseases, such as chronic obstructive pulmonary disease (COPD), are frequently associated with rhinovirus (RV) infections. Despite these associations, the pathogenesis of virus-induced exacerbations is incompletely understood. We aimed to investigate effects of cigarette smoke (CS), a primary risk factor for COPD, on RV infection in airway epithelium and identify novel mechanisms related to these effects. Methods Primary bronchial epithelial cells (PBEC) from COPD patients and controls were differentiated by culture at the air-liquid interface (ALI) and exposed to CS and RV-A16. Bulk RNA sequencing was performed using samples collected at 6 and 24 h post infection (hpi), and viral load, mediator and l-lactate levels were measured at 6, 24 and 48hpi. To further delineate the effect of CS on RV-A16 infection, we performed growth differentiation factor 15 (GDF15) knockdown, l-lactate and interferon pre-treatment in ALI-PBEC. We performed deconvolution analysis to predict changes in the cell composition of ALI-PBEC after the various exposures. Finally, we compared transcriptional responses of ALI-PBEC to those in nasal epithelium after human RV-A16 challenge. Results CS exposure impaired antiviral responses at 6hpi and increased viral replication at 24 and 48hpi in ALI-PBEC. At 24hpi, CS exposure enhanced expression of RV-A16-induced epithelial interferons, inflammation-related genes and CXCL8. CS exposure increased expression of oxidative stress-related genes, of GDF15, and decreased mitochondrial membrane potential. GDF15 knockdown experiments suggested involvement of this pathway in the CS-induced increase in viral replication. Expression of glycolysis-related genes and l-lactate production were increased by CS exposure, and was demonstrated to contribute to higher viral replication. No major differences were demonstrated between COPD and non-COPD-derived cultures. However, cellular deconvolution analysis predicted higher secretory cells in COPD-derived cultures at baseline. Conclusion Altogether, our findings demonstrate that CS exposure leads to higher viral infection in human bronchial epithelium by altering not only interferon responses, but likely also through a switch to glycolysis, and via GDF15related pathways.Pathogenesis and treatment of chronic pulmonary disease

Higher diagnostic accuracy and cost-effectiveness using procalcitonin in the treatment of emergency medicine patients with fever (The HiTEMP study)

__Background:__ Fever is a common symptom in the emergency department(ED). Fever can be caused by bacterial infections, which are treated with antibiotics. Often, bacterial infections cannot be ruled out in the ED using standard diagnostics, and empiric antibiotic treatment is started. Procalcitonin(PCT) is a biomarker for bacterial infections, but its role in an undifferentiated ED population remains unclear. We hypothesize that PCT-guided therapy may reduce antibiotics prescription in undifferentiated febrile ED patients. The primary objectives of this study are to determine a) the efficacy, b) the safety of PCT-guided therapy, and c) the accuracy of the biomarker PCT for bacterial infections. The secondary objective is to study the cost-effectiveness of PCT-guided therapy. __Methods/design:__ This is a multicenter noninferiority randomized controlled trial. All adult ED patients with fever(≥38.2 °C) are randomized between standard care with and without the addition of a PCT level, after written informed consent. a) For efficacy, the reduction of patients receiving antibiotics is calculated, using a superiority analysis: differences between the PCT-guided group and control group are assessed using a Fisher's exact test, and a multivariable logistic regression analysis to account for the effects of demographic and medical variables on the percentage of febrile patients receiving antibiotics. b) Safety consists of a composite endpoint, defined as mortality, intensive care admission and ED return visit within 14 days. Noninferiority of PCT will be tested using a one-sided 95 % confidence interval for the difference in the composite safety endpoint between the PCT-guided and control groups using a noninferiority margin of 7.5 %. c) Accuracy of PCT and CRP for the diagnosis of bacterial infections will be reported, using the sensitivity, specificity, and the area under the receiver-operating-characteristic curve in the definitive diagnosis of bacterial infections. The sample size is 550 patients, which was calculated using a power analysis for all primary objectives. Enrollment of patients started in August 2014 and will last 2 years. __Discussion:__ PCT may offer a more tailor-made treatment to the individual ED patient with fever. Prospective costs analyses will reveal the economic consequences of implementing PCT-guided therapy in the ED. This trial is registered in the Dutch trial register:NTR4949

A Rare Case of the Digenic Inheritance of Long QT Syndrome Type 2 and Type 6

We report a 37-year-old woman with an out-of-hospital cardiac arrest caused by ventricular fibrillation due to digenic inheritance of long QT syndrome type 2 (KCNH2 gene) and type 6 (KCNE2 gene). During hospitalization, prolonged QTc intervals and frequent episodes of ventricular tachyarrhythmias manifested. Genetic testing identified a mutation of the KCNH2 gene and an unclassified variant, most likely pathogenic, of the KCNE2 gene. This digenic inheritance is extremely rare

Outcome prediction of electroconvulsive therapy for depression

Introduction: We developed and tested a Bayesian network(BN) model to predict ECT remission for depression, with non-response as a secondary outcome. Methods: We performed a systematic literature search on clinically available predictors. We combined these predictors with variables from a dataset of clinical ECT trajectories (performed in the University Medical Center Utrecht) to create priors and train the BN. Temporal validation was performed in an independent sample. Results: The systematic literature search yielded three meta-analyses, which provided prior knowledge on outcome predictors. The clinical dataset consisted of 248 treatment trajectories in the training set and 44 trajectories in the test set at the same medical center. The AUC for the primary outcome remission estimated on an independent validation set was 0.686 (95%CI 0.513–0.859) (AUC values of 0.505 – 0.763 observed in 5-fold cross validation of the model within the train set). Accuracy 0.73 (balanced accuracy 0.67), sensitivity 0.55, specificity 0.79, after temporal validation in the independent sample. Prior literature information marginally reduced CI width. Discussion: A BN model comprised of prior knowledge and clinical data can predict remission of depression after ECT with reasonable performance. This approach can be used to make outcome predictions in psychiatry, and offers a methodological framework to weigh additional information, such as patient characteristics, symptoms and biomarkers. In time, it may be used to improve shared decision-making in clinical practice

Sinus Rhythm Conduction Properties across Bachmann's Bundle: Impact of Underlying Heart Disease and Atrial Fibrillation

Valvular heart disease (VHD) is a common risk factor for atrial fibrillation (AF). Conduction abnormalities (CA) during sinus rhythm (SR) across Bachmann’s bundle (BB) are associated with AF development. The study goal is to compare electrophysiological characteristics across BB during SR between patients with ischemic (IHD) and/or VHD either with or without ischemic heart disease ((I)VHD), with/without AF history using high-resolution intraoperative epicardial mapping. In total, 304 patients (IHD: n = 193, (I)VHD: n = 111) were mapped; 40 patients (13%) had a history of AF. In 116 patients (38%) there was a mid-entry site with a trend towards more mid-entry sites in patients with (I)VHD vs. IHD (p = 0.061), whereas patients with AF had significant more mid-entry sites than without AF (p = 0.007). CA were present in 251 (95%) patients without AF compared to 39 (98%) with AF. The amount of CA was comparable in patients with IHD and (I)VHD (p > 0.05); AF history was positively associated with the amount of CA (p < 0.05). Receiver operating characteristic (ROC) curve showed 85.0% sensitivity and 86.4% specificity for cut-off values of CA lines of respectively ≤ 6 mm and ≥ 26 mm. Patients without a mid-entry site or long CA lines (≥ 12 mm) were unlikely to have AF (sensitivity 90%, p = 0.002). There are no significant differences in entry-sites of wavefronts and long lines of CA between patients with IHD compared to (I)VHD. However, patients with AF have more wavefronts entering in the middle of BB and a higher incidence of long CA lines compared to patients without a history of AF. Moreover, in case of absence of a mid-entry site or long line of CA, patients most likely have no history of AF

Asian dust-storm activity dominated by Chinese dynasty changes since 2000 BP

The Asian monsoon (AM) played an important role in the dynastic history of China, yet it remains unknown whether AM-mediated shifts in Chinese societies affect earth surface processes to the point of exceeding natural variability. Here, we present a dust storm intensity record dating back to the first unified dynasty of China (the Qin Dynasty, 221–207 B.C.E.). Marked increases in dust storm activity coincided with unified dynasties with large populations during strong AM periods. By contrast, reduced dust storm activity corresponded to decreased population sizes and periods of civil unrest, which was co-eval with a weakened AM. The strengthened AM may have facilitated the development of Chinese civilizations, destabilizing the topsoil and thereby increasing the dust storm frequency. Beginning at least 2000 years ago, human activities might have started to overtake natural climatic variability as the dominant controls of dust storm activity in eastern China

Guided self-help on the internet for turkish migrants with depression: the design of a randomized controlled trial

Background The Turkish population living in the Netherlands has a high prevalence of psychological complaints and has a high threshold for seeking professional help for these problems. Seeking help through the Internet can overcome these barriers. This project aims to evaluate the effectiveness of a guided self-help problem-solving intervention for depressed Turkish migrants that is culturally adapted and web-based. Methods This study is a randomized controlled trial with two arms: an experimental condition group and a wait list control group. The experimental condition obtains direct access to the guided web-based self-help intervention, which is based on Problem Solving Treatment (PST) and takes 6 weeks to complete. Turkish adults with mild to moderate depressive symptoms will be recruited from the general population and the participants can choose between a Turkish and a Dutch version. The primary outcome measure is the reduction of depressive symptoms, the secondary outcome measures are somatic symptoms, anxiety, acculturation, quality of life and satisfaction. Participants are assessed at baseline, post-test (6 weeks), and 4 months after baseline. Analysis will be conducted on the intention-to-treat sample. Discussion This study evaluates the effectiveness of a guided problem-solving intervention for Turkish adults living in the Netherlands that is culturally adapted and web-based