Comparison of two non-bronchoscopic methods for evaluating inflammation in patients with acute hypoxaemic respiratory failure

INTRODUCTION: The simple bedside method for sampling undiluted distal pulmonary edema fluid through a normal suction catheter (s-Cath) has been experimentally and clinically validated. However, there are no data comparing non-bronchoscopic bronchoalveolar lavage (mini-BAL) and s-Cath for assessing lung inflammation in acute hypoxaemic respiratory failure. We designed a prospective study in two groups of patients, those with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and those with acute cardiogenic lung edema (ACLE), designed to investigate the clinical feasibility of these techniques and to evaluate inflammation in both groups using undiluted sampling obtained by s-Cath. To test the interchangeability of the two methods in the same patient for studying the inflammation response, we further compared mini-BAL and s-Cath for agreement of protein concentration and percentage of polymorphonuclear cells (PMNs). METHODS: Mini-BAL and s-Cath sampling was assessed in 30 mechanically ventilated patients, 21 with ALI/ARDS and 9 with ACLE. To analyse agreement between the two sampling techniques, we considered only simultaneously collected mini-BAL and s-Cath paired samples. The protein concentration and polymorphonuclear cell (PMN) count comparisons were performed using undiluted sampling. Bland-Altman plots were used for assessing the mean bias and the limits of agreement between the two sampling techniques; comparison between groups was performed by using the non-parametric Mann-Whitney-U test; continuous variables were compared by using the Student t-test, Wilcoxon signed rank test, analysis of variance or Student-Newman-Keuls test; and categorical variables were compared by using chi-square analysis or Fisher exact test. RESULTS: Using protein content and PMN percentage as parameters, we identified substantial variations between the two sampling techniques. When the protein concentration in the lung was high, the s-Cath was a more sensitive method; by contrast, as inflammation increased, both methods provided similar estimates of neutrophil percentages in the lung. The patients with ACLE showed an increased PMN count, suggesting that hydrostatic lung edema can be associated with a concomitant inflammatory process. CONCLUSIONS: There are significant differences between the s-Cath and mini-BAL sampling techniques, indicating that these procedures cannot be used interchangeably for studying the lung inflammatory response in patients with acute hypoxaemic lung injury.

Comparison of multiplex ligation-dependent probe amplification and real-time PCR accuracy for gene copy number quantification using the beta-defensin locus

The reliable quantification of gene copy number variations is a precondition for future investigations regarding their functional relevance. To date, there is no generally accepted gold standard method for copy number quantification, and methods in current use have given inconsistent results in selected cohorts. In this study, we compare two methods for copy number quantification. beta-defensin gene copy numbers were determined in parallel in 80 genomic DNA samples by real-time PCR and multiplex ligation-dependent probe amplification (MLPA). The pyrosequencing-based paralog ratio test (PPRT) was used as a standard of comparison in 79 out of 80 samples. Realtime PCR and MPLA results confirmed concordant DEFB4, DEFB103A, and DEFB104A copy numbers within samples. These two methods showed identical results in 32 out of 80 samples; 29 of these 32 samples comprised four or fewer copies. The coefficient of variation of MLPA is lower compared with PCR. In addition, the consistency between MLPA and PPRT is higher than either PCR/MLPA or PCR/PPRT consistency. In summary, these results suggest that MLPA is superior to real-time PCR in beta-defensin copy number quantification.

Class-switzched B cells display response to therapeutic B-cell depletion in rheumatoid arthritis

Introduction Reconstitution of peripheral blood (PB) B cells after therapeutic depletion with the chimeric anti-CD20 antibody rituximab (RTX) mimics lymphatic ontogeny. In this situation, the repletion kinetics and migratory properties of distinct developmental B-cell stages and their correlation to disease activity might facilitate our understanding of innate and adaptive B-cell functions in rheumatoid arthritis (RA). Methods Thirty-five 'RTX-naïve' RA patients with active arthritis were treated after failure of tumour necrosis factor blockade in an open-label study with two infusions of 1,000 mg RTX. Prednisone dose was tapered according to clinical improvement from a median of 10 mg at baseline to 5 mg at 9 and 12 months. Conventional disease-modifying antirheumatic drugs were kept stable. Subsets of CD19+ B cells were assessed by flow cytometry according to their IgD and CD27 surface expression. Their absolute number and relative frequency in PB were followed every 3 months and were determined in parallel in synovial tissue (n = 3) or synovial fluid (n = 3) in the case of florid arthritis. Results Six of 35 patients fulfilled the European League Against Rheumatism criteria for moderate clinical response, and 19 others for good clinical response. All PB B-cell fractions decreased significantly in number (P < 0.001) after the first infusion. Disease activity developed independently of the total B-cell number. B-cell repopulation was dominated in quantity by CD27-IgD+ 'naïve' B cells. The low number of CD27+IgD- class-switched memory B cells (MemB) in the blood, together with sustained reduction of rheumatoid factor serum concentrations, correlated with good clinical response. Class-switched MemB were found accumulated in flaring joints. Conclusions The present data support the hypothesis that control of adaptive immune processes involving germinal centre-derived, antigen, and T-cell-dependently matured B cells is essential for successful RTX treatment.

A tutorial on data-driven methods for statistically assessing ERP topographies

Dynamic changes in ERP topographies can be conveniently analyzed by means of microstates, the so-called "atoms of thoughts", that represent brief periods of quasi-stable synchronized network activation. Comparing temporal microstate features such as on- and offset or duration between groups and conditions therefore allows a precise assessment of the timing of cognitive processes. So far, this has been achieved by assigning the individual time-varying ERP maps to spatially defined microstate templates obtained from clustering the grand mean data into predetermined numbers of topographies (microstate prototypes). Features obtained from these individual assignments were then statistically compared. This has the problem that the individual noise dilutes the match between individual topographies and templates leading to lower statistical power. We therefore propose a randomization-based procedure that works without assigning grand-mean microstate prototypes to individual data. In addition, we propose a new criterion to select the optimal number of microstate prototypes based on cross-validation across subjects. After a formal introduction, the method is applied to a sample data set of an N400 experiment and to simulated data with varying signal-to-noise ratios, and the results are compared to existing methods. In a first comparison with previously employed statistical procedures, the new method showed an increased robustness to noise, and a higher sensitivity for more subtle effects of microstate timing. We conclude that the proposed method is well-suited for the assessment of timing differences in cognitive processes. The increased statistical power allows identifying more subtle effects, which is particularly important in small and scarce patient populations.

A connection between two nonparametric tests for perfect ranking in balanced ranked set sampling

In this note, we show that an extension of a test for perfect ranking in a balanced ranked set sample given by Li and Balakrishnan (2008) to the multi-cycle case turns out to be equivalent to the test statistic proposed by Frey et al. (2007). This provides an alternative interpretation and motivation for their test statistic.

Time courses and quantitative analysis of atrial fibrillation episode number and duration after circular plus linear left atrial lesions: trigger elimination or substrate modification: early or delayed cure?

OBJECTIVES We sought to analyze the time course of atrial fibrillation (AF) episodes before and after circular plus linear left atrial ablation and the percentage of patients with complete freedom from AF after ablation by using serial seven-day electrocardiograms (ECGs). BACKGROUND The curative treatment of AF targets the pathophysiological corner stones of AF (i.e., the initiating triggers and/or the perpetuation of AF). The pathophysiological complexity of both may not result in an "all-or-nothing" response but may modify number and duration of AF episodes. METHODS In patients with highly symptomatic AF, circular plus linear ablation lesions were placed around the left and right pulmonary veins, between the two circles, and from the left circle to the mitral annulus using the electroanatomic mapping system. Repetitive continuous 7-day ECGs administered before and after catheter ablation were used for rhythm follow-up. RESULTS In 100 patients with paroxysmal (n = 80) and persistent (n = 20) AF, relative duration of time spent in AF significantly decreased over time (35 +/- 37% before ablation, 26 +/- 41% directly after ablation, and 10 +/- 22% after 12 months). Freedom from AF stepwise increased in patients with paroxysmal AF and after 12 months measured at 88% or 74% depending on whether 24-h ECG or 7-day ECG was used. Complete pulmonary vein isolation was demonstrated in <20% of the circular lesions. CONCLUSIONS The results obtained in patients with AF treated with circular plus linear left atrial lesions strongly indicate that substrate modification is the main underlying pathophysiologic mechanism and that it results in a delayed cure instead of an immediate cure.

Monitoring of Urinary Calcium and Phosphorus Excretion in Preterm Infants - Comparison of two Methods

OBJECTIVES: Premature babies require supplementation with calcium and phosphorus to prevent metabolic bone disease of prematurity. To guide mineral supplementation, two methods of monitoring urinary excretion of calcium and phosphorus are used: urinary calcium or phosphorus concentration and calcium/creatinine or phosphorus/creatinine ratios. We compare these two methods in regards to their agreement on the need for mineral supplementation. METHODS: Retrospective chart review of 230 premature babies with birthweight <1500 g, undergoing screening of urinary spot samples from day 21 of life and fortnightly thereafter. Hypothetical cut-off values for urine calcium or phosphorus concentration (1 mmol/l) and urine calcium/creatinine ratio (0.5 mol/mol) or phosphorus/creatinine ratio (4 mol/mol) were applied to the sample results. The agreement on whether or not to supplement the respective minerals based on the results with the two methods was compared. Multivariate general linear models sought to identify patient characteristic to predict disagreeing results. RESULTS: 24.8% of cases disagreed on the indication for calcium supplementation, 8.8% for phosphorus. Total daily calcium intake was the only patient characteristic associated with discordant results. CONCLUSIONS: With the intention to supplement the respective mineral, comparison of urinary mineral concentration with mineral/creatinine ratio is moderate for Calcium and good for Phosphorus. The results do not allow to identify superiority of either method on the decision which babies require calcium and/or phosphorus supplements.

Imported diphyllobothriasis in Switzerland: molecular methods to define a clinical case of Diphyllobothrium infection as Diphyllobothrium dendriticum, August 2010

Following a first clinical case of infection by Diphyllobothrium dendriticum in Switzerland in 2006, we report a second case in the country. The species was identified by molecular methods. In the Swiss, French and Italian subalpine regions, human diphyllobothriasis has seen a comeback since the late 1980's, and Diphyllobothrium latum is usually considered the causative agent of the disease. In addition, several locally acquired and imported clinical infections due to allochthonous Diphyllobothrium species have been documented in the last years. Due to the colonisation potential of these parasites and their probably underestimated presence in the human population, there is a need for discriminating them at the medical laboratory level. Because the morphological characters are very similar among the different taxa, a correct identification requires the use of molecular methods. Molecular identification would improve diagnosis and help monitor the distribution of Diphyllobothrium species in Europe.

A fuzzy risk attitude classification based on prospect theory

Traditional methods do not actually measure peoples’ risk attitude naturally and precisely. Therefore, a fuzzy risk attitude classification method is developed. Since the prospect theory is usually considered as an effective model of decision making, the personalized parameters in prospect theory are firstly fuzzified to distinguish people with different risk attitudes, and then a fuzzy classification database schema is applied to calculate the exact value of risk value attitude and risk be- havior attitude. Finally, by applying a two-hierarchical clas- sification model, the precise value of synthetical risk attitude can be acquired.

The International ADHD in Substance Use Disorders Prevalence (IASP) study: background, methods and study population

Attention deficit/hyperactivity disorder (ADHD) is an increasingly recognized comorbid condition in subjects with substance use disorders (SUDs). This paper describes the methods and study population of the International ADHD in Substance Use Disorders Prevalence (IASP) study. Objectives of the IASP are to determine the prevalence of ADHD in adult treatment seeking patients with SUD in different countries and SUD populations, determine the reliability and validity of the Adult ADHD Self-report Scale V 1.1 (ASRS) as ADHD screening instrument in SUD populations, investigate the comorbidity profile of SUD patients with and without ADHD, compare risk factors and protective factors in SUD patients with and without a comorbid diagnosis of ADHD, and increase our knowledge about the relationship between ADHD and the onset and course of SUD. In this cross-sectional, multi-centre two stage study, subjects were screened for ADHD with the ASRS, diagnosed with the Conner's Adult ADHD Diagnostic Interview for DSM-IV (CAADID), and evaluated for SUD, major depression, bipolar disorder, anti social personality disorder and borderline personality disorder. Three thousand five hundred and fifty-eight subjects from 10 countries were included. Of these 40.9% screened positive for ADHD. This is the largest international study on this population evaluating ADHD and comorbid disorders.

Image and imaging an emergency department: expense and benefit of different quality assessment methods

Introduction. In this era of high-tech medicine, it is becoming increasingly important to assess patient satisfaction. There are several methods to do so, but these differ greatly in terms of cost, time, and labour and external validity. The aim of this study is to describe and compare the structure and implementation of different methods to assess the satisfaction of patients in an emergency department. Methods. The structure and implementation of the different methods to assess patient satisfaction were evaluated on the basis of a 90-minute standardised interview. Results. We identified a total of six different methods in six different hospitals. The average number of patients assessed was 5012, with a range from 230 (M5) to 20 000 patients (M2). In four methods (M1, M3, M5, and M6), the questionnaire was composed by a specialised external institute. In two methods, the questionnaire was created by the hospital itself (M2, M4).The median response rate was 58.4% (range 9-97.8%). With a reminder, the response rate increased by 60% (M3). Conclusion. The ideal method to assess patient satisfaction in the emergency department setting is to use a patient-based, in-emergency department-based assessment of patient satisfaction, planned and guided by expert personnel.

Vandetanib in locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 2 trial

BACKGROUND No effective standard treatment exists for patients with radioiodine-refractory, advanced differentiated thyroid carcinoma. We aimed to assess efficacy and safety of vandetanib, a tyrosine kinase inhibitor of RET, VEGFR and EGFR signalling, in this setting. METHODS In this randomised, double-blind, phase 2 trial, we enrolled adults (aged ≥18 years) with locally advanced or metastatic differentiated thyroid carcinoma (papillary, follicular, or poorly differentiated) at 16 European medical centres. Eligible patients were sequentially randomised in a 1:1 ratio with a standard computerised scheme to receive either vandetanib 300 mg per day (vandetanib group) or matched placebo (placebo group), balanced by centre. The primary endpoint was progression-free survival (PFS) in the intention-to-treat population based on investigator assessment. This study is registered with ClinicalTrials.gov, number NCT00537095. FINDINGS Between Sept 28, 2007, and Oct 16, 2008, we randomly allocated 72 patients to the vandetanib group and 73 patients to the placebo group. By data cutoff (Dec 2, 2009), 113 (78%) patients had progressed (52 [72%] patients in the vandetanib group and 61 [84%] in the placebo group) and 40 (28%) had died (19 [26%] patients in the vandetanib group and 21 [29%] in the placebo group). Patients who received vandetanib had longer PFS than did those who received placebo (hazard ratio [HR] 0·63, 60% CI 0·54-0·74; one-sided p=0·008): median PFS was 11·1 months (95% CI 7·7-14·0) for patients in the vandetanib group and 5·9 months (4·0-8·9) for patients in the placebo group. The most common grade 3 or worse adverse events were QTc prolongation (ten [14%] of 73 patients in the vandetanib group vs none in the placebo group), diarrhoea (seven [10%] vs none), asthenia (five [7%] vs three [4%]), and fatigue (four [5%] vs none). Two patients in the vandetanib group and one in the placebo group died from treatment-related serious adverse events (haemorrhage from skin metastases and pneumonia in the vandetanib group and pneumonia in the placebo group). INTERPRETATION Vandetanib is the first targeted drug to show evidence of efficacy in a randomised phase 2 trial in patients with locally advanced or metastatic differentiated thyroid carcinoma. Further investigation of tyrosine-kinase inhibitors in this setting is warranted. FUNDING AstraZeneca.

Somatostatin-based radiotherapy with [90Y-DOTA]-TOC in neuroendocrine tumors: long-term outcome of a phase I dose escalation study

BACKGROUND We describe the long-term outcome after clinical introduction and dose escalation of somatostatin receptor targeted therapy with [90Y-DOTA]-TOC in patients with metastasized neuroendocrine tumors. METHODS In a clinical phase I dose escalation study we treated patients with increasing [90Y-DOTA]-TOC activities. Multivariable Cox regression and competing risk regression were used to compare efficacy and toxicities of the different dosage protocols. RESULTS Overall, 359 patients were recruited; 60 patients were enrolled for low dose (median: 2.4 GBq/cycle, range 0.9-7.8 GBq/cycle), 77 patients were enrolled for intermediate dose (median: 3.3 GBq/cycle, range: 2.0-7.4 GBq/cycle) and 222 patients were enrolled for high dose (median: 6.7 GBq/cycle, range: 3.7-8.1 GBq/cycle) [90Y-DOTA]-TOC treatment. The incidences of hematotoxicities grade 1-4 were 65.0%, 64.9% and 74.8%; the incidences of grade 4/5 kidney toxicities were 8.4%, 6.5% and 14.0%, and the median survival was 39 (range: 1-158) months, 34 (range: 1-118) months and 29 (range: 1-113) months. The high dose protocol was associated with an increased risk of kidney toxicity (Hazard Ratio: 3.12 (1.13-8.59) vs. intermediate dose, p = 0.03) and a shorter overall survival (Hazard Ratio: 2.50 (1.08-5.79) vs. low dose, p = 0.03). CONCLUSIONS Increasing [90Y-DOTA]-TOC activities may be associated with increasing hematological toxicities. The dose related hematotoxicity profile of [90Y-DOTA]-TOC could facilitate tailoring [90Y-DOTA]-TOC in patients with preexisting hematotoxicities. The results of the long-term outcome suggest that fractionated [90Y-DOTA]-TOC treatment might allow to reduce renal toxicity and to improve overall survival. (ClinicalTrials.gov number NCT00978211).

Towards a taxonomy of common factors in psychotherapy-results of an expert survey

BACKGROUND: How change comes about is hotly debated in psychotherapy research. One camp considers 'non-specific' or 'common factors', shared by different therapy approaches, as essential, whereas researchers of the other camp consider specific techniques as the essential ingredients of change. This controversy, however, suffers from unclear terminology and logical inconsistencies. The Taxonomy Project therefore aims at contributing to the definition and conceptualization of common factors of psychotherapy by analyzing their differential associations to standard techniques. METHODS: A review identified 22 common factors discussed in psychotherapy research literature. We conducted a survey, in which 68 psychotherapy experts assessed how common factors are implemented by specific techniques. Using hierarchical linear models, we predicted each common factor by techniques and by experts' age, gender and allegiance to a therapy orientation. RESULTS: Common factors differed largely in their relevance for technique implementation. Patient engagement, Affective experiencing and Therapeutic alliance were judged most relevant. Common factors also differed with respect to how well they could be explained by the set of techniques. We present detailed profiles of all common factors by the (positively or negatively) associated techniques. There were indications of a biased taxonomy not covering the embodiment of psychotherapy (expressed by body-centred techniques such as progressive muscle relaxation, biofeedback training and hypnosis). Likewise, common factors did not adequately represent effective psychodynamic and systemic techniques. CONCLUSION: This taxonomic endeavour is a step towards a clarification of important core constructs of psychotherapy. KEY PRACTITIONER MESSAGE: This article relates standard techniques of psychotherapy (well known to practising therapists) to the change factors/change mechanisms discussed in psychotherapy theory. It gives a short review of the current debate on the mechanisms by which psychotherapy works. We provide detailed profiles of change mechanisms and how they may be generated by practice techniques.

State of Emergency Medicine in Switzerland: a national profile of emergency departments in 2006

BACKGROUND Emergency departments (EDs) are an essential component of any developed health care system. There is, however, no national description of EDs in Switzerland. Our objective was to establish the number and location of EDs, patient visits and flow, medical staff and organization, and capabilities in 2006, as a benchmark before emergency medicine became a subspecialty in Switzerland. METHODS In 2007, we started to create an inventory of all hospital-based EDs with a preliminary list from the Swiss Society of Emergency and Rescue Medicine that was improved with input from ED physicians nationwide. EDs were eligible if they offered acute care 24 h per day, 7 days per week. Our goal was to have 2006 data from at least 80% of all EDs. The survey was initiated in 2007 and the 80% threshold reached in 2012. RESULTS In 2006, Switzerland had a total of 138 hospital-based EDs. The number of ED visits was 1.475 million visits or 20 visits per 100 inhabitants. The median number of visits was 8,806 per year; 25% of EDs admitted 5,000 patients or less, 31% 5,001-10,000 patients, 26% 10,001-20,000 patients, and 17% >20,000 patients per year. Crowding was reported by 84% of EDs with >20,000 visits/year. Residents with limited experience provided care for 77% of visits. Imaging was not immediately available for all patients: standard X-ray within 15 min (70%), non-contrast head CT scan within 15 min (38%), and focused sonography for trauma (70%); 67% of EDs had an intensive care unit within the hospital, and 87% had an operating room always available. CONCLUSIONS Swiss EDs were significant providers of health care in 2006. Crowding, physicians with limited experience, and the heterogeneity of emergency care capabilities were likely threats to the ubiquitous and consistent delivery of quality emergency care, particularly for time-sensitive conditions. Our survey establishes a benchmark to better understand future improvements in Swiss emergency care.